Endothelin receptor antagonists

ABSTRACT

Novel indane and indene derivatives are described which are endothelin receptor antagonists.

This is a divisional of application Ser. No. 09/574,413 filed May 19,2000 now U.S. Pat. No. 6,274,737, which is a divisional of 09/099,373,filed Jun. 18, 1998 now U.S. Pat. No. 6,087,389; which is a divisionalof application Ser. No. 08/336,444, filed Nov. 9, 1994 now U.S. Pat. No.5,817,693; which is a continuation-in-part of International ApplicationPCT/US 94/04603, filed Apr. 26, 1994; which is a continuation-in-part ofapplication Ser. No. 08/066,818, filed Apr. 27, 1993 (now abandoned);which is a continuation-in-part of International Application PCT/US92/09427, filed Oct. 29, 1992; which is a continuation-in-part of Ser.No. 07/854,195 filed Mar. 20, 1992 (now abandoned), which is acontinuation-in-part of Ser. No. 07/787,870 filed Nov. 5, 1991 (nowabandoned).

FIELD OF INVENTION

The present invention relates to novel indane and indene derivatives,pharmaceutical compositions containing these compounds and their use asendothelin receptor antagonists.

Endothelin (ET) is a highly potent vasoconstrictor peptide synthesizedand released by the vascular endothelium. Endothelin exists as threeisoforms, ET-1, ET-2 and ET-3. [Unless otherwise stated “endothelin”shall mean any or all of the isoforms of endothelin]. Endothelin hasprofound effects on the cardiovascular system, and in particular, thecoronary, renal and cerebral circulation. Elevated or abnormal releaseof endothelin is associated with smooth muscle contraction which isinvolved in the pathogenesis of cardiovascular, cerebrovascular,respiratory and renal pathophysiology. Elevated levels of endothelinhave been reported in plasma from patients with essential hypertension,acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis,and patients with uraemia undergoing dialysis.

In vivo, endothelin has pronounced effects on blood pressure and cardiacoutput. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in ratscauses a transient, dose-related depressor response (lasting 0.5 to 2minutes) followed by a sustained, dose-dependent rise in arterial bloodpressure which can remain elevated for 2 to 3 hours following dosing.Doses above 3 nmol/kg in a rat often prove fatal.

Endothelin appears to produce a preferential effect in the renalvascular bed. It produces a marked, long-lasting decrease in renal bloodflow, accompanied by a significant decrease in GFR, urine volume,urinary sodium and potassium excretion. Endothelin produces a sustainedantinatriuretic effect, despite significant elevations in atrialnatriuretic peptide. Endothelin also stimulates plasma renin activity.These findings suggest that ET is involved in the regulation of renalfunction and is involved in a variety of renal disorders including acuterenal failure, cyclosporine nephrotoxicity, radio contrast induced renalfailure and chronic renal failure.

Studies have shown that in vivo, the cerebral vasculature is highlysensitive to both the vasodilator and vasoconstrictor effects ofendothelin. Therefore, ET may be an important mediator of cerebralvasospasm, a frequent and often fatal consequence of subarachnoidhemorrhage.

ET also exhibits direct central nervous system effects such as severeapnea and ischemic lesions which suggests that ET may contribute to thedevelopment of cerebral infarcts and neuronal death.

ET has also been implicated in myocardial ischernia (Nichols etal. Br.J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Circ. Res., 65:1193-1200, 1989) coronary vasospasm (Fukuda et al., Eur. J. Pharm. 165:301-304, 1989 and Lüscher, Circ. 83: 701, 1991) heart failure,proliferation of vascular smooth muscle cells, (Takagi, Biochem &Biophys. Res. Commun.; 168: 537-543, 1990, Bobek et al., Am. J. Physiol,258:408-C 415, 1990) and atherosclerosis, (Nakaki et al., Biochem. &Biophys. Res. Commun. 158: 880-881, 1989, and Lerman et al., New Eng. J.of Med. 325: 997-1001, 1991). Increased levels of endothelin have beenshown after coronary balloon angioplasty (Kadel et al., No. 2491 Circ.82: 627, 1990).

Further, endothelin has been found to be a potent constrictor ofisolated mammalian airway tissue including human bronchus (Uchida etal., Eur J. of Pharm. 154: 227-228 1988, LaGente, Clin. Exp. Allergy 20:343-348, 1990; and Springall et al., Lancet, 337: 697-701, 1991).Endothelin may play a role in the pathogenesis of interstitial pulmonaryfibrosis and associated pulmonary hypertension, Glard et al., ThirdInternational Conference on Endothelin, 1993, p. 34 and ARDS (AdultRespiratory Distress Syndrome), Sanai et al., Supra, p. 112.

Endothelin has been associated with the induction of hemorrhagic andnecrotic damage in the gastric mucosa (Whittle et al., Br. J. Pharm. 95:1011-1013, 1988); Raynaud's phenomenon, Cinniniello et al., Lancet 337:114-115, 1991); Crohn's Disease and ulcerative colitis, Munch et al.,Lancet, Vol. 339, p. 381; Migraine (Edmeads, Headache, February 1991 p127); Sepsis (Weitzberg et al., Circ. Shock 33: 222-227, 1991; Pittet etal., Ann. Surg. 213: 262-264, 1991), Cyclosporin-induced renal failureor hypertension (Eur. J. Pharmacol., 180: 191-192, 1990, Kidney Int, 37:1487-1491, 1990) and endotoxin shock and other endotoxin induceddiseases (Biochem. Biophvs. Res. Commun., 161: 1220-1227, 1989, ActaPhysiol. Scand. 137: 317-318, 1989) and inflammatory skin diseases,(Clin Res. 41:451 and 484, 1993) and macular degeneration.

Endothelin has also been implicated in preclampsia of pregnancy. Clarket al., Am. J. Obstet. Gynecol, March 1992, p. 962-968; Kamor et al., N.Eng. J. of Med., Nov. 22, 1990, p. 1486-1487; Dekker et al., Eur J. Ob.and Gyn. and Rep. Bio. 40 (1991) 215-220; Schiff et al., Am. J. Obstet.Gynecol. February 1992, p. 624-628; diabetes mellitus, Takahashi et al.,Diabetologia (1990) 33:306-310; and acute vascular rejection followingkidney transplant, Watschinger et al., Transplantation Vol. 52, No. 4,pp. 743-746.

Endothelin stimulates both bone resorption and anabolism and may have arole in the coupling of bone remodeling. Tatrai et al. Endocrinology,Vol. 131, p. 603-607.

Endothelin has been reported to stimulate the transport of sperm in theuterine cavity, Casey et al., J. Clin. Endo and Metabolism, Vol. 74, No.1, p. 223-225, therefore endothelin antagonists may be useful as malecontraceptives. Endothelin modulates the ovarian/menstrual cycle,Kenegsberg, J. of Clin. Endo. and Met., Vol. 74, No. 1, p. 12, and mayalso play a role in the regulation of penile vascular tone in man, Lauet al., Asia Pacific J. of Pharm., 1991, 6:287-292 and Tejada et al., J.Amer. Physio. Soc. 1991, H1078-1085. Endothelin also mediates a potentcontraction of human prostatic smooth muscle, Langenstroer et al., J.Urology, Vol. 149, p. 495-499.

Thus, endothelin receptor antagonists would offer a unique approachtoward the pharmacotherapy of hypertension, renal failure, ischemiainduced renal failure, sepsis-endotoxin induced renal failure,prophylaxis and/or treatment of radio-contrast induced renal failure,acute and chronic cyclosporin induced renal failure, cerebrovasculardisease, myocardial ischemia, angina, congestive heart failure, asthma,atherosclerosis, macular degeneration, Raynaud's phenomenon, ulcers,sepsis, migraine, glaucoma, endotoxin shock, endotoxin induced multipleorgan failure or disseminated intravascular coagulation,cyclosporin-induced renal failure and as an adjunct in angioplasty forprevention or treatment of restenosis, diabetes, preclampsia ofpregnancy, bone remodeling, kidney transplant, male contraceptives,infertility and priaprism and benign prostatic hypertrophy.

SUMMARY OF THE INVENTION

This invention comprises indane and indene derivatives represented byFormula (I) and pharmaceutical compositions containing these compounds,and their use as endothelin receptor antagonists which are useful in thetreatment of a variety of cardiovascular and renal diseases includingbut not limited to: hypertension, acute and chronic renal failure,cyclosporine induced nephrotoxicity, stroke, cerebrovascular vasospasm,myocardial ischemia, angina, heart failure, atherosclerosis, and as anadjunct in angioplasty for prevention of restenosis and benign prostatichypertrophy.

This invention further constitutes a method for antagonizing endothelinreceptors in an animal, including humans, which comprises administeringto an animal in need thereof an effective amount of a compound ofFormula (I).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by structural Formula(I):

wherein:

R₁ is —X(CH₂)_(n)Ar or —X(CH₂)_(n)R₈ or

R₂ is hydrogen, Ar, C₁₋₄alkyl or (c);

P₁ is —X(CH₂)_(n)R₈;

P₂ is —X(CH₂)_(n)R₈, or —X—R₉—Y;

R₃ and R₅ are independently hydrogen, R₁₁, OH, C₁₋₈alkoxy, S(O)_(q)R₁₁,N(R₆)₂, Br, F, I, Cl, CF₃, NHCOR₆, R₁₃CO₂R₇, —X—R₉—Y, or —X(CH₂)_(n)R₈wherein each methylene group within —X(CH₂)_(n)R₈ may be unsubstitutedor substituted by one or two —(CH₂)_(n)Ar groups;

R₄ is hydrogen, R₁₁, OH, C₁₋₅alkoxy, S(O)_(q)R₁₁, N(R₆)₂, Br, F, I, Clor NHCOR₆ wherein the C₁₋₅alkoxy may be unsubstituted or substituted byOH, methoxy or halogen;

R₆ is independently hydrogen or C₁₋₄alkyl;

R₇ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₈alkynyl,all of which may be unsubstituted or substituted by one or more OH,N(R6)2, CO2R12, halogen or XC1- 5alkyl; or R7 is (CH2) nAr;

R8 is hydrogen, R11, CO2R7, CO2C(R11)2 O(CO)XR7, PO3(R7)2, SO₂NR₇R₁₁,NR₇SO₂R₁₁, CONR₇SO₂R₁₁, SO₃R₇, SO₂R₇, P(O)(OR₇)R₇, CN,—CO₂(CH₂)_(m)C(O)N(R₆)₂, C(R₁₁)₂N(R₇)₂, C(O)N(R₆)₂, tetrazole or OR₆;

R₉ is a bond, C₁₋₁₀alkylene, C₁₋₁₀alkenylene, C₁₋₁₀alkylidene,C₁₋₁₀alkynylene, all of which may be linear or branched, or phenylene,all of which may be unsubstituted or substituted by one or more OH,N(R₆)₂, COOH or halogen;

R₁₀ is R₃or R₄;

R₁₁ is hydrogen, Ar, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, all of whichmay be unsubstituted or substituted by one or more OH, CH₂OH, N(R₆)₂ orhalogen;

R₁₂ is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₇alkynyl;

R₁₃ is divalent Ar, C₁₋₁₀alkylene, C₁₋₁₀alkylidene, C₂₋₁₀alkenylene,C₂₋₁₀alkynylene, all of which may be unsubstituted or substituted by oneor more OH, CH₂OH, N(R₆)₂ or halogen;

X is (CH₂)_(n), O, NR₆ or S(O)_(q);

Y is CH₃ or X(CH₂)_(n)Ar;

Ar is:

naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl,isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl,imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl,morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all ofwhich may be unsubstituted or substituted by one or more R₃ or R₄groups;

A is C═O, or (C(R₆)₂)_(m) ;

B is —CH₂—or —O—;

Z₁ and Z₂ are independently hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, OH, C₁₋₈alkoxy, S(O) q C₁₋₈alkyl, N(R₆)₂, Br, F, I, Cl,NHCOR₆, —X—R₉—Y, —X(CH₂)_(n)R₈, phenyl, benzyl or C₃₋₆cycloalkyl whereinthe C₁₋₈alkyl, C₂₋₈alkenyl or C₂₋₈alkynyl may be optionally substitutedby COOH, OH, CO(CH₂)_(n)CH₃, CO(CH₂)_(n)CH₂N(R₆)₂, or halogen; or Z₁ andZ₂ together may be —O—A—O— on contiguous carbons;

Z₃ is Z₁ or —X—R₉—Y;

q is zero, one or two;

n is an integer from 0 to six;

m is 1, 2 or 3;and the dotted line indicates the optional presence of adouble bond; or a pharmaceutically acceptable salt thereof; providedthat

R₂ is not hydrogen when X is S(O)_(q);

when the optional double bond is present there is only one R₁₀ and thereis no P₁ and P₂ is not NR₆R₉Y; and if X—R₂ is attached to the doublebond, X is not NR₆; and if R₁ is attached directly to the double bond,R₁ is not NR₆AR;

when R₃, R₅, Z₁, Z₂, or Z₃ is X(CH₂)_(n)R₈ and n is not 0, X is oxygenor NR₆ when R₈ is OR₆ or CO₂H;

when R₈ is CO₂C(R₁₁)₂O(CO)XR₇, X is not S(O)_(q);

the compound of Formula I is not (1RS)-1,3-diphenylindene-2-carboxylicacid; (cis,cis)-(1RS,3SR)-1,3-diphenylindane-2-carboxylic acid;(1RS)-3-[3-Methyl-1-phenyl-(1H)-ind-2-en-1-yl] propionic acid; or(1RS)-2-[1,3-diphenyl-(1H)-ind-2-en-2-yl]ethanoic acid;1,3-diphenyl-1-ethoxyindene-2-carboxylic acid; 1,2,3-triphenylindene;1,3 diphenylindene; 1-(2,3-dimethyl-2-buten-yl)-1,3-diphenylindene;1,3-diphenyl-2-methylindene; 1,3-diphenyl-2-methylindane;1,3-diphenylindane; 5,6-dimethoxy-1,3-dimethoxyindene;1,3-bis(4,5-dimethoxy-2-hydroxyphenyl)-5,6-dimethoxyindane;1,3-bis(3,4-dimethoxyphenyl)-5,6-dimethoxyindane;1,3-diphenyl-2-methoxyidene, 1,3-diphenyl-2-ethoxyindene,5-fluoro-2-methyl-indene-3-acetic acid, methyl1,3-diphenylindene-2-carboxylate, ethyl1,3-diphenylindene-2-carboxylate, or 2-cyano-1,3-diphenylindene.

Also included in the invention are pharmaceutically acceptable saltcomplexes. Preferred are the ethylene diamine, sodium, potassium,calcium and ethanolarnine salts.

The term alkylene is a divalent alkyl group in which the bonds are ontwo different carbon atoms; alkylidene is a divalent alkyl group inwhich the bonds are on the same carbon atom; alkenylene is a divalentalkene group in which the bonds may be on any carbon atom; alkynylene isa divalent alkynyl group in which the bonds may be on any carbon atom.

All alkyl, alkenyl, alkynyl, alkoxy, alkylene, alkylidene, alkenyleneand alkynylene groups may be straight or branched. The term “halogen” isused to mean iodo, fluoro, chloro or bromo. Alkyl groups may besubstituted by one or more halogens up to perhalocenation.

The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeform. All of these compounds and diastereoisomers are contemplated to bewithin the scope of the present invention.

Preferred compounds are those wherein R₁ is X(CH₂)_(n)Ar, (Ar is (a) or(b)), dihydrobenzofuranyl, benzodioxanyl, cyclohexyl or C₁₋₄alkyl; R₂ isa moiety of formula (a) or (b), C₁₋₄alkyl, indolyl or hydrogen; R₃ andR₅ are independently hydrogen, OH, C₁₋₅alkoxy, halogen, —OC₁₋₄alkylphenyl, R₁₃CO₂R₇, C₁₋₄alkyl, N(R₆)₂, NH(CO)CH₃, —X(CH₂)_(n)R₈, —X—R₉—Ypyridyl, phenyl or S(O)_(p)C₁₋₅alkyl; R₄ is hydrogen, OH, C₁₋₅alkoxy,halogen, C₁₋₄alkyl, N(R₆)₂, NH(CO)CH₃ or S(O)_(p)C₁₋₅alkyl; Z₁, Z₂ andZ₃ are independently XR₉Y, benzyl, hydrogen, OH, C₁₋₅alkoxy, —N(R₆)₂,S(O)qC₁₋₈alkyl, NHCOR₆, X(CH₂)_(n)R₈ or halogen, or Z₁ and Z₂ togethermay be —O—A—O on contiguous carbons; P₁ and P₂ are independentlyhydrogen, CO₂H, C(R₆)₂CO₂H or tetrazole; Ar is a moiety of formula (a)or (b), phenyl, or pyridyl; X is (CH₂)_(n) or oxygen.

More preferred are compounds wherein R₃ is hydrogen, —X(CH₂)_(n)R₈ orR₁₃CO₂R₇; R₄ and R₅ are independently hydrogen, OH, C₁₋₅alkoxy,SC₁₋₅alkyl, substituted phenyl, F, Br, C₁₋₃alkyl or NH₂; Z₁ and Z₃ arehydrogen and Z₂ is hydrogen, OH, C₁₋₅alkoxy, halogen, X(CH₂)_(n)R₈, NH₂,benzyl, NH(CO)CH₃, or Z₁ and Z₂ together may be O—A—O on contiguouscarbons and R₁, R₂, P₁, P₂, Ar and X are as above for preferredcompounds.

Most preferred are compounds wherein R₁ is (b) and R₂ is (a) or (b); Ais CH₂, B is —O—; there is no optional double bond; R₁ and XR₂ are transto P₁; Z₂ is hydrogen, OH, C₁₋₅alkoxy, or —OCH₂CH═CH₂, Z₁ is hydrogen;R₃ is XAr, hydrogen, X(CH₂)_(n)COOH, X(CH₂)_(n)CONR₇SO₂R₁₁,X[(CR₆)₂]_(n)OR₆ or CH═CHCO₂H; R₄ is hydrogen, substituted phenyl,pyridyl or pyrimidyl, or C₁₋₂alkoxy; R₅, R₁₀ and P₂ are hydrogen, and P₁is CO₂H or C(R₆)₂CO₂H.

Especially preferred are compounds wherein R₁ is (b) and R₂ is (a); A isCH₂, B is —O—; there is no optional double bond; R₁ and XR₂ are trans toP₁; X is a bond; Z₁ and Z₃ are hydrogen; Z₂ is hydrogen, OH orC₁₋₅alkoxy; R₃ is hydrogen, OAr (where Ar is (a), (b), pyridyl orpyrimidyl and A is CH₂ and B is —O— and Ar may be substituted by CO₂H),O(CH₂)₁₋₃CO₂H, O(CH₂)₁₋₃CONHSO₂R₁₁, (CH₂)₀₋₄CO₂H, (CH₂)₀₋₃CONH SO₂R₁₁,or O[(CR₆)₂]₂₋₄ OH; R₄ is hydrogen, C₁₋₂alkoxy, or phenyl, pyridyl orpyrimridyl all of which may be substituted by R₃ or C₁₋₂alkoxy; R₅, R₁₀and P₂ are hydrogen; and P₁ is CO₂H or CH₂CO₂H.

Especially preferred compounds are the following:

(1RS,2SR,3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid;

(+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid;

(+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid disodium salt;

(1RS,2SR,3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(2-methoxy-4,5-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid;

(1RS,2SR,3RS)-3-[2-(2-Carboxyeth-1-yloxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid;

(1RS,2SR,3SR)-3-[2-[(E)-2-Carboxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid;

(1RS,2SR,3SR)-3-[2-(2-Carboxyeth-1-yl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid;

(1RS,2SR,3RS)-3-[2-(3-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid;

(+)(1S,2R,3S)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;

(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;

(1RS,2SR,3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;

(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatehemiethylenediamine salt;

(1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-yl-aceticacid.

(1RS,2SR,3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-ylacetic acid

The present invention provides compounds of Formula (I) above

which can be prepared by a process which comprises:

a) reacting a compound of Formula (2) wherein X is C₁₋₅alkyl

with a substituted benzaldehyde or aldehyde of Formula (3).

D—CHO  (3)

wherein D is Ar or (c) as defined in Formula I, in a suitable solventsuch as benzene with a catalyst such as piperidinium acetate at refluxto provide a compound of Formula (4).

Cyclization of compound (4) in the presence of a suitable Lewis acidsuch as titanium tetracholoride or aluminum chloride or alternativelywhen Z₁ is 3-OR (meta)(where R is C₁₋₅alkyl, or benzyl), trifluoroaceticacid, provides an indanone of the Formula (5).

Dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in anappropriate solvent or alternatively bromination with pyridiniumhydrobromide perbromide in dichloromethane followed by treatment with1,5-diazabicyclo[4,3,0]non-5-ene provides indenones of Formula (6).

b) Alternatively, a compound of Formula 6 wherein Z₁, Z₂ and Z₃ arehydrogen and

can be prepared by treatment of 2-bromobenzoic acid with two equivalentsof n-butyllithium in a solvent such as tetrahydrofuran under argon at−78° C. followed by the addition of an acid chloride of Formula (7):

provides a compound of Formula (8):

Treatment of compounds of type (8) with thionyl chloride at reflux givesan acid chloride which can be isolated by concentration under reducedpressure. This acid chloride can then be treated with diethyl magnesiummalonate in a solvent such as ether to give a compound of Formula (9):

Reaction of a compound of type (9) at reflux with 5% aqueous sodiumcarbonate gives compounds of Formula (10):

c) Treatment of an indenone of Formula (11):

wherein Z₁, Z₂, Z₃ and R₁ are as defined for formula I or a groupconvertable to them, with an organomagnesium compound of Formula (12)wherein R₂ is defined for

R₂(CH₂)_(n)MgBr  (12)

Formula I or a group convertable to it, in a suitable solvent providescompounds of Formula (13):

Saponification of compounds of Formula (13) using sodium hydroxide inaqueous methanol followed by reduction with triethylsilane and borontrifluoride etherate in a suitable solvent such as dichloromethane at 0°C. affords racemic compounds of Formula (14).

Conjugate addition of nucleophiles to an ester derived from Formula(14), followed by saponification affords compounds of Formula (I) havingan R₁₀ other than hydrogen. Re-introduction of a double bond into anester derived from such acids followed by conjugate addition of anothernucleophilic species and subsequent saponification affords compounds ofFormula (1) in which neither R₁₀ substituent is hydrogen.

Reduction of compounds of Formula (13) with triethylsilane and borontrifluoride etherate in a suitable solvent such as dichloromethane at 0°C. followed by hydrogenation with hydrogen gas under pressure atapproximately 60 psi in the presence of a suitable catalyst such as 10%palladium on charcoal affords compounds of Formula (15):

Alkylation or acylation of the ester enolate derived from Formula (15)affords compounds wherein P₁ and P₂ are as defined in Formula (I).

Alternatively, hydrogenation of compounds of Formula (13) with hydrogengas under pressure at approximately 60 psi in the presence of a suitablecatalyst such as 10% palladium on charcoal in a suitable solvent such asethyl acetate or methanol containing 1-5% acetic acid affords compoundsof Formula (15). Treatment of these compounds with a base such as sodiumhydroxide in a suitable solvent such as aqueous ethanol provides racemiccompounds of Formula (16):

wherein Z₁, Z₂ and Z₃ are hydrogen; R₁=R₂; and n is 0. Treatment ofcompounds of Formula (13) with triethylsilane and boron trifluorideetherate in a suitable solvent such as dichloromethane at 0° C. followedby reaction with samarium II iodide in a suitable solvent such astetrahydrofuran and then saponification, provides compounds of Formula(17)

With appropriate manipulation and protection of any chemicalfunctionalities, synthesis of the remaining compounds of the Formula (I)is accomplished by methods analogous to those above and to thosedescribed in the Experimental section.

In order to use a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals itis normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

Compounds of Formula (1) and their pharmaceutically acceptable salts maybe administered in a standard manner for the treatment of the indicateddiseases, for example orally, parenterally, sub-lingually,transdermally, rectally, via inhalation or via buccal administration.

Compounds of Formula (1) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as syrups, tablets,capsules and lozenges. A syrup formulation will generally consist of asuspension or solution of the compound or salt in a liquid carrier forexample, ethanol, peanut oil, olive oil, glycerine or water with aflavouring or colouring agent. Where the composition is in the form of atablet, any pharmaceutical carrier routinely used for preparing solidformulations may be used. Examples of such carriers include magnesiumstearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid,starch, lactose and sucrose. Where the composition is in the form of acapsule, any routine encapsulation is suitable, for example using theaforementioned carriers in a hard gelatin capsule shell. Where thecomposition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example aqueous gums, celluloses,silicates or oils and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous or non-aqueous carrieroptionally containing a parenterally acceptable oil, for examplepolyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, orsesame oil.

Typical compositions for inhalation are in the form of a solution,suspension or emulsion that may be administered as a dry powder or inthe form of an aerosol using a conventional propellant such asdichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (1) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats or their synthetic analogues.

Typical transdermal formulations comprise a conventional aqueous ornon-aqueous vehicle, for example a cream, ointment, lotion or paste orare in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer tothemselves a single dose.

Each dosage unit for oral administration contains suitably from 0.1 mgto 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosageunit for parenteral administration contains suitably from 0.1 mg to 100mg/Kg, of a compound of Formula (1) or a pharmaceutically acceptablesalt thereof calculated as the free acid. Each dosage unit forintranasal administration contains suitably 1-400 mg and preferably 10to 200 mg per person. A topical formulation contains suitably 0.01 to5.0% of a compound of Formula (I).

The daily dosage regimen for oral administration is suitably about 0.01mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for parenteral administration is suitably about 0.001 mg/Kg to40 mg/Kg, of a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for intranasal administration and oral inhalation is suitablyabout 10 to about 500 mg/person. The active ingredient may beadministered from 1 to 6 times a day, sufficient to exhibit the desiredactivity.

No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the present invention.

The biological activity of the compounds of Formula (I) are demonstratedby the following tests:

I. Binding Assay

A) Membrane Preparation (Rat cerebellum or kidney cortex)

Rat cerebellum or kidney cortex were rapidly dissected and frozenimmediately in liquid nitrogen or used fresh. The tissues, 1-2 g forcerebellum or 3-5 g for kidney cortex, were homogenized in 15 mls ofbuffer containing 20 mM Tris HCl and 5 mM EDTA, pH 7.5 at 4° C. using amotor-driven homogenizer. The homogenates were filtered throughcheesecloth and centrifuged at 20,000×g for 10 minutes at 4° C. Thesupernatant was removed and centrifuged at 40,000×g for 30 minutes at 4°C. The resulting pellet was resuspended in a small volume of buffercontaining 50 mM Tris, 10 mM MgCl₂, pH 7.5; aliquotted with small vialsand frozen in liquid nitrogen. The membranes were diluted to give 1 and5 micrograms of protein for each tube for cerebellum and kidney cortexin the binding assay.

Freshly isolated rat mesenteric artery and collateral vascular bed werewashed in ice cold saline (on ice) and lymph nodes were removed fromalong the major vessel. Then, the tissue was homogenized using apolytron in buffer containing 20 mM Tris and 5mM EDTA, pH 7.5 at 4° C.in 15 ml volume for ˜6 gm of mesenteric artery bed. The homogenate wasstrained through cheesecloth and centrifuged at 2,000×g for 10 min. at4° C. The supernatant was removed and centrifuged at 40,000×g for 30min. at 4° C. The resulting pellet was resuspended as explained abovefor cerebellum and kidney cortex. Approximately 10 micrograms ofmembrane protein was used for each tube in binding experiments.

B) CHO Cell Membrane Preparation

CHO cells stably transfected with human ET_(A) and ET_(B) receptors weregrown in 245 mm×245 mm tissue culture plates in Dulbecco's modifiedEagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS).The confluent cells were washed with DPBS (Dulbecco's phosphate bufferedsaline) containing protease inhibitor cockatil (5 mM EDTA, 0.5 mM PMSF,5 ug/ml leupeptin, and 0.1 U/ml aprotinin) and scraped in the samebuffer. After centrifugation at 800×g, the cells were lysed by freezingin liquid nitrogen and thawing on ice followed by homogenization (30times using glass dounce homogenizer) in lysis buffer containing 20 mMTris HCl, pH 7.5 and the protease inhibitor cocktail. After an initialcentrifugation at 800×g for 10 min to remove unbroken cells and nuclei,the supernatants were centrifuged at 40,000×g for 15 min and the pelletwas resuspended in 50 mM Tris HCl, pH 7.5 and 10 mM MgCl₂ and stored insmall aliquots at −70° C. after freezing in liquid N₂. Protein wasdetermined using BCA method and bovine serum albumin as the standard.

C) [¹²⁵I]ET-1 Binding Protocol

[¹²⁵I]ET-1 binding to membranes from rat cerebellum (2-5 mgprotein/assay tube) or kidney cortex (3-8 micrograms protein/assay tube)or CHO cell membranes (containing 4-6 and 1-2 micrograms of membraneprotein for ET_(A) and ET_(B) receptors, respectively) were measuredafter 60 minutes incubation at 30° C. in 50 mM Tris HCl, 10 mM MgCl₂,0.05% BSA, pH 7.5 buffer in a total volume of 100 microliters. Membranep rotein was added to tubes containing either buffer or indicatedconcentration of compounds. [¹²⁵I]ET-1 (2200 Ci/mmol) was diluted in thesame buffer containing BSA to give a final concentration of 0.2-0.5 nMET-1. Total and nonspecific binding were measured in the absence andpresence of 100 nM unlabelled ET-1. After the incubation, the reactionswere stopped with 3.0 ml cold buffer containing 50 mM Tris and 10 mMMgCl₂, pH 7.5. Membrane bound radioactivity was separated from freeligand by filtering through Whatman GF/C filter paper and washing thefilters 5 times with 3 ml of cold buffer using a Brandel cell harvester.Filter papers were counted in a gamma counter with an efficiency of 75%.IC₅₀'s for the compounds of this invention range from 0.01 nm to 50 uM.

II. In Vitro Vascular Smooth Muscle Activity

Rat aorta are cleaned of connective tissue and adherent fat, and cutinto ring segments approximately 3 to 4 mm in length. Vascular rings aresuspended in organ bath chambers (10 ml) containing Krebs-bicarbonatesolution of the following composition (millimolar): NaCl, 112.0; KC1,4.7; KH₂PO₄, 1.2; MgSO₄, 1.2; CaCl₂, 2.5; NaHCO₃, 25.0; and dextrose,11.0. Tissue bath solutions are maintained at 37° C. and aeratedcontinuously with 95% O₂/5% CO₂. Resting tensions of aorta aremaintained at 1 g and allowed to equilibrate for 2 hrs., during whichtime the bathing solution is changed every 15 to 20 min. Isometrictensions are recorded on Beckman R-611 dynographs with Grass FT03force-displacement transducer. Cumulative concentration-response curvesto ET-1 or other contractile agonists are constructed by the method ofstep-wise addition of the agonist. ET-1 concentrations are increasedonly after the previous concentration produces a steady-statecontractile response. Only one concentration-response curve to ET-1 isgenerated in each tissue. ET receptor antagonists are added to pairedtissues 30 min prior to the initiation of the concentration-response tocontractile agonists.

ET-1 induced vascular contractions are expressed as a percentage of theresponse elicited by 60 mM KCl for each individual tissue which isdetermined at the beginning of each experiment. Data are expressed asthe mean ±S.E.M. Dissociation constants (K_(b)) of competitiveantagonists were determined by the standard method of Arunlakshana andSchild. The potency range for compounds of this invention range from0.01 nM to 50 uM.

The following examples are illustrative and are not limiting of thecompounds of this invention.

EXAMPLE 1 (1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylicacid

a) Ethyl(1RS)[1-Hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate. Todry magnesium turnings (0.88 g, 36 mmol) under an argon atmosphere wasadded, portionwise, a solution of p-bromoanisole (4.5 ml, 36 mmol) in 5%THF/Et₂O (37 ml). The resulting p-methoxyphenyt magnesium bromidesolution was added to a solution of ethyl1-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in Et₂O (300 ml)under an argon atmosphere at 0° C. The resulting mixture was allowed towarm to room temperature and was stirred for 10 min. The mixture waspartitioned between 3M HCl (100 ml) and EtOAc (200 ml). The organicextract was washed successively with H₂O, aqueous NaHCO₃, H₂O andsaturated aqueous NaCl and dried (Na₂SO₄). The solvent was removed invacuo to provide a yellow oil which was treated with Et₂O/ hexanes. Thesolid which formed was collected by filtration (3.47 g). The filtratewas concentrated under reduced pressure and purified by flashchromatography. The material which was isolated was treated with Et₂O/hexanes, and the additional solid which formed (1.76 g, 75% total yield)was collected by filtration to afford the title compound.

b) Ethyl (RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylate. To asolution of ethyl (1RS)[1-hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate (4.65 g,12.0 mmol) in CH₂Cl₂ (40 ml) at 0° C. under an argon atmosphere wasadded triethylsilane (2.34 ml, 14.6 mmol), followed by boron trifluorideetherate (8.8 ml, 71 mmol). The reaction mixture was allowed to warm toroom temperature and stirred for 10 min, at which time was added slowly3M HCl (50 ml). The mixture was extracted with EtOAc (150 ml). Theorganic extract was washed successively with H₂O, aqueous NaHCO₃, H₂Oand saturated aqueous NaCl and dried. The solvent was removed in vacuo,and the residue was purified by flash chromatography on silica gel,eluting with 10% EtOAc/ hexanes to provide the title compound (4.2 g,95%) as a mixture of Δ1 and Δ2 double bond isomers.

c) Ethyl (1RS,2SR,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylate.To a solution of ethyl(RS)-1-(4-methoxyphenyl)-3-phenylindene-2-carboxylate (5.75 g, 15 mmol)in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg).The resulting suspension was stirred under an atmosphere of H₂ for 1 d,then was filtered through a pad of Celite. The filtrate was concentratedunder reduced pressure to afford the title compound, which was usedwithout further purification.

d) (1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylic acid.To a solution of ethyl (1RS,2SR,3SR)-1-(4-methoxyphenyl)-3-phenylindane-2-carboxylate, (5.5 g, 14.8mmol) in EtOH (70 ml) was added 5M NaOH (9 ml, 45 mmol). The resultingmixture was stirred under an argon atmosphere for 1 d, at which time H₂O(70 ml) was added. The mixture was concentrated under reduced pressure.The aqueous residue was extracted with Et₂O, and the Et₂O extracts werediscarded. The aqueous phase was acidified with 6M HCl and extractedseveral times with EtOAc. The combined EtOAc extracts were washedsuccessively with H₂O and saturated aqueous NaCl and dried. The solventwas removed in vacuo to provide an oily residue which crystallized uponstanding. The solid material was recrystallized from EtOAc/ hexanes toafford the title compound (4.25 g, 83%); m.p. 164 -166° C.

¹H NMR (CDCl₃): δ7.35- 7.18 (m, 9H); 6.92-6.88 (m, 4H); 4.68 (d, 1H,J=10 Hz); 4.64 (d, 1H, J=10 Hz); 3.81 (s, 3H); 3.34 (t, 1H, J=10 Hz).MS: 345 [(M+H)₊]. Anal. Calc. for C₂₃H₂₀O₃: C, 80.21; H, 5.85. Found C,80.21; H 6.03.

EXAMPLE 2 (trans, trans)-1,3-Di(4-methoxyphenyl)-indane-2-carboxylicacid

a) Ethyl 2-Benzoyl-3-(4-hydroxyphenyl)propenoate. To a solution of4-hydroxybenzaldehyde (31.7 g, 0.26 mol) and ethyl benzoylacetate (45.5ml, 0.26 mol) in EtOH (45 ml) under an argon atmosphere was addedpiperidine (2.6 ml, 0.026 mol) and acetic acid (3 drops). After stirringat room temperature overnight, the resulting solid mixture was treatedwith hot EtOH (700 ml), and then allowed to cool. The crystals whichformed were collected by filtration to afford the title compound (61.0g, 79%).

b) Ethyl (2RS,3SR)-3-(4-Hydroxyphenyl)-1-oxoindane-2-carboxylate. To amixture of ethyl 2-benzoyl-3-(4-hydroxyphenyl)propenoate (0.50 g, 1.7mmol) in CH₂Cl₂ (15 ml) at 0° C. under an argon atmosphere was addedtitanium tetrachloride (0.93 ml, 8.3 mmol). The resulting mixture wasallowed to stir at room temperature overnight. The reaction was slowlyquenched with 3M HCl, then partitioned between EtOAc (50 ml) and 3M HCl.The aqueous phase was extracted with EtOAc, and the combined organicextracts were washed successively with H₂O and saturated aqueous NaCl,and dried (Na₂SO₄). The solvent was removed in vacuo, and the solidresidue was recrystallized from EtOAc/hexanes to afford the titlecompound (410 mg, 82%).

c) Ethyl(2RS,3SR)-3-(4-t-Butyldimethylsiloxyphenyl)-1-oxoindane-2-carboxylate.To a solution of ethyl(2RS,3SR)-3-(4-hydroxyphenyl)-1-oxoindane-2-carboxylate (3.0 g, 10.2mmol) in DMF (10 ml) under an argon atmosphere were added imidazole(1.72 g, 25.3 mmol) and t-butyldimethylchloro-silane (1.82 g, 12.1mmol). The resulting mixture was allowed to stir at room temperature for3 d, then was poured into dilute aqueous HCl and extracted with EtOAc(2×). The combined organic extracts were washed successively with H₂Oaqueous NaHCO₃, H₂O and saturated aqueous NaCl and dried. The solventwas removed in vacuo to provide the title compound (5.40 g) which wasused without further purification.

d) Ethyl 3-(4-t-Butyldimethylsiloxyphenyl)-1-oxoindene-2-carboxylate. Toa solution of ethyl(2RS,3SR)-3-(4-t-butyldimethylsiloxyphenyl)-1-oxoindane-2-carboxylate(130 mg, 0.32 mmol) in CH₂Cl₂ (3 ml) under an argon atmosphere was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35 mmol). Theresulting mixture was stirred for 2.5 h. Aqueous NaHSO₃ and EtOAc wereadded, and the mixture was stirred for 5 min. The aqueous phase wasseparated and extracted with EtOAc, and the combined organic extractswere washed successively with aqueous NaHCO₃, H₂O and saturated aqueousNaCl and dried. The solvent was removed in vacuo, and the residue waspurified by flash chromatography on silica gel to afford the titlecompound (110 mg, 85%).

e) Ethyl(1RS)-3-(4-t-Butyldimethylsiloxyphenyl)-1-hydroxy-1-(4-methoxyphenyl)indene-2-carboxylate.To dry magnesium turnings (119 mg, 4.9 mmol) under an argon atmospherewas added, portionwise, a solution of p-bromoanisole (0.61 ml, 4.9 mmol)in 9: 1 Et₂O/ THF (10 ml). The resulting p-methoxyphenyl magnesiumbromide solution was added to a solution of ethyl3-(4-t-butyldimethylsiloxyphenyl)-1-oxoindene-2-carboxylate (1.00 g, 2.5mmol) in Et₂O (60 ml) under an argon atmosphere at 0° C. The resultingmixture was allowed to warm to room temperature and was stirred for 5min. The mixture was partitioned between 3M HCl and EtOAc. The organicextract was washed successively with H₂O aqueous NaHCO₃, H₂O andsaturated aqueous NaCl and dried. The solvent was removed in vacuo toprovide the title compound (1.47 g) which was used without furtherpurification.

f) Ethyl(RS)-1-hydroxy-(4-t-Butyldimethylsiloxyphenyl)-3-(4-methoxyphenyl)indene-2-carboxylate.To a solution of ethyl(1RS)-3-(4-t-butyldimethylsiloxyphenyl)-1-hydroxy-1-(4-methoxyphenyl)indene-2-carboxylate(2.5 mmol, prepared above) in CH₂Cl₂ (10 ml) at 0° C. under an argonatmosphere was added triethylsilane (0.48 ml, 3.0 mmol), followed byboron trifluoride etherate (1.8 ml, 14.6 mmol). The reaction mixture wasallowed to warm to room temperature and stirred for 10 min, at whichtime was added slowly 3M HCl. The mixture was extracted with EtOAc. Theorganic extract was washed successively with H₂O, aqueous NaHCO₃, H₂Oand saturated aqueous NaCl and dried. The solvent was removed in vacuo,and the residue was purified by flash chromatography on silica gel,eluting with 15% Et₂O/hexanes to provide the title compound as a mixtureof Δ1 and Δ2 double bond isomers (820 mg, 67% for two steps).

g) Ethyl(1RS,2SR,3SR)-1-(4-t-Butyldimethyl-siloxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate.To a solution of ethyl(RS)-3-(4-t-butyldimethylsiloxyphenyl)-1-(4-methoxyphenyl)indane-2-carboxylate(mixture of Δ1 and Δ2 double bond isomers) (750 mg, 1.5 mmol) in EtOH(25 ml) was added 5% palladium on activated carbon (70 mg). Theresulting suspension was stirred under an atmosphere of H₂ for 18 h,then was filtered through a pad of Celite. The filtrate was concentratedunder reduced pressure to afford the title compound (730 mg, 97%), whichwas used without further purification.

h) Ethyl(1RS,2RS,3SR)-1-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate.To a solution of ethyl(1RS,2SR,3SR)-1-(4-t-butyldimethylsiloxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate(723 mg, 1.4 mmol) in EtOH (20 ml) was added 1M NaOH (1.6 ml, 1.6 mmol),and the resulting mixture was stirred at room temperature for 30 min.The mixture was then partitioned between 3M HCl and EtOAc. The aqueousphase was extracted with EtOAc, and the combined organic extracts werewashed successively with H₂O and saturated aqueous NaCl and dried. Thesolvent was removed in vacuo to afford the title compound (554 mg,100%).

i) Ethyl (cis, cis)-1.3-Di(4-methoxyphenyl)indane-2-carboxylate. To asolution of ethyl(1RS,2RS,3SR)-1-(4-hydroxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate(270 mg, 0.7 mmol) in acetonitrile (5 ml) at 0° C. was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 ml, 1.7 mmol), followed bymethyl iodide (0.5 ml, 8.0 mmol). The resulting mixture was allowed towarm to room temperature and was stirred overnight. The mixture waspartitioned between EtOAc and dilute aqueous HCl. The organic extractwas washed with saturated aqueous NaCl and dried. The solvent wasremoved in vacuao, and the residue was purified by flash chromatographyto afford the title compound (40 mg, 32% based on recovered startingmaterial).

j) (trans, trans)-1,3-Di(4-methoxyphenyl)indane-2-carboxylic acid. To asolution of ethyl (cis, cis)-1,3-di(4-methoxyphenyl)indane-2-carboxylate(35 mg, 0.09 mmol) in EtOH (3 ml) was added 1M NaOH (0.25 ml, 0.25mmol), and the resulting mixture was allowed to stir at room temperatureovernight. Thin layer chromatographic analysis at this time indicatedthat the reaction was incomplete, so 5M NaOH (0.15 ml, 0.75 mmol) wasadded, and the mixture was allowed to stand at 0° C. for 5 days. Waterwas added, and the mixture was concentrated under reduced pressure. Theaqueous residue was extracted with Et₂O (2×), and the Et₂O extracts werediscarded. The aqueous phase was acidified with 6M HCl and extractedseveral times with EtOAc. The combined EtOAc extracts were washedsuccessively with H₂O and saturated aqueous NaCl and dried. The solventwas removed in vacuo to provide an oily residue which crystallized uponstanding. The solid material was recrystallized from EtOAc/hexanes toafford the title compound (19 mg, 59%); m.p. 192-193° C.

¹H NMR (acetone-d₆): δ7.21-7.18 (m, 2H); 6.92 (dd, 4H, J=6.6 Hz, 2.1Hz); 6.86-6.83 (m, 2H); 4.59 (d, 2H, J=10 Hz); 3.79 (s, 6H); 3.26 (t,1H, J=10 Hz). MS: 392 [(M+NH₄)₊]. Anal. Calc. for C₂₄H₂₂O₄: C, 76.99; H,5.92. Found C, 76.74; H 6.15.

EXAMPLE 3 (1RS,2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid

a) 2-(3,4-Methylenedioxybenzoyl)benzoic acid. To a solution of2-bromobenzoic acid (12 g, 0.06 mol) in THF (200 ml) at −100° C. underan argon atmosphere was added dropwise n-butyl lithium (50 ml of 2.5Msolution in hexanes, 0.125 mol), maintaining the temperature below −90°C. Upon completion of the addition, the resulting solution was stirredat −100° C. for 1 h, at which time was added slowly a solution ofpiperonylic acid chloride (11 g, 0.06 mol) in THF (50 ml), maintainingthe temperature below −90° C. The resulting mixture was allowed to warmto −80° C. and stirred for 1 h, then was allowed to slowly warm to roomtemperature and left to stand for 48 h. The reaction mixture wasconcentrated under reduced pressure, and the residue was partitionedbetween Et₂O and 1M HCl. The organic phase was extracted with 10%aqueous NaOH. The NaOH extract was acidified with concentrated HCl, andthe combined aqueous material was extracted with Et₂O. The Et₂O extractwas dried (MgSO₄) and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel, eluting with asolvent gradient of 10-30% EtOAc/0.1% HOAc/hexanes to afford the titlecompound as an off-white solid (4.5 g, 28%).

b) Diethyl 2-[2-(3,4-Methylenedioxybenzoyl)benzoyl-malonate. A solutionof 2-(3,4-methylenedioxybenzoyl)-benzoic acid (4.0 g, 14.8 mmol) inthionyl chloride (30 ml) was heated at reflux for 2 h, then allowed tocool and was concentrated under reduced pressure. The residue wasdissolved in Et₂O (50 ml) and to this was added a solution of diethylmagnesium malonate [prepared by the method of Walker and Hauser, JACS,68, 1386 (1946) using magnesium (0.8 g, 33.3 mmol) and diethyl malonate(4.9 g, 30.6 mmol)] in Et₂O. The resulting mixture was heated at refluxfor 1 h, then allowed to cool and was poured into ice-cold 10% aqueousH₂SO₄ (100 ml). The aqueous phase was extracted with Et₂O, and thecombined organic material was washed with saturated aqueous NaCl anddried. The solvent was removed under reduced pressure to afford thetitle compound as an orange oil, which was used without furtherpurification.

c) Ethyl 3-(3,4-Methylenedioxyphenyl)-1-oxoindene-2-carboxylate. Asolution containing diethyl2-[2-(3,4-methylenedioxybenzoyl)benzoylmalonate (crude material preparedabove) in 5% aqueous Na₂CO₃ (100 ml) was heated at reflux for 10 min.The reaction mixture was then allowed to cool, and the aqueous materialwas removed by decantation. The residue was placed in H₂O (50 ml), andthe mixture was heated at reflux, cooled and concentrat-ed under reducedpressure. The residue was recrystallized from hexanes to afford thetitle compound as a yellow solid (5.0 g, 100% for two steps).

d) Ethyl(1RS)-1-Hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate.A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9: 1 Et₂O/ THF (10ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and theresulting mixture was allowed to stir for 30 min. The resultant4-methoxyphenyl magnesium bromide was added dropwise to a solution ofethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g,2.4 mmol) in 10 : 1 Et₂O/ THF (55 ml) at 0° C. The resulting mixture wasstirred at 0° C. for 1 h and was then partitioned between EtOAc and 1MHCl. The aqueous phase was extracted with EtOAc, and the combinedorganic extracts were washed successively with 5% aqueous NaHCO₃ andsaturated aqueous NaCl and dried (MgSO₄). The solvent was removed underreduced pressure, and the residue was purified by flash chromatographyon silica gel, eluting with 10% EtOAc/ hexanes to afford the titlecompound as a yellow glassy solid (0.80 g, 80%).

e) Ethyl(RS)-1-(4-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate.To a solution of ethyl(1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate(0.80 g, 1.9 mmol) in CH₂Cl₂ (10 ml) at 0° C. under an argon atmospherewas added triethylsilane (0.28 g, 2.4 mmol), followed by borontrifluoride etherate (1 ml, 8.1 mmol). The resulting solution wasstirred at 0° C. for 10 min, and was then partitioned between EtOAc and3M HCl. The organic extract was washed with saturated aqueous NaCl anddried (MgSO₄). The solvent was removed in vacua, and the residue wasfiltered through a pad of silica gel, eluting with CH₂CH₂. The titlecompound (mixture of Δ1 and Δ2 double bond isomers) was obtained as aglassy, yellow solid (0.72 g, 94%).

f) Ethyl(1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate.To a solution of ethyl(RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate(0.72 g, 1.7 mmol) in EtOH (30 ml) was added 10% palladium on activatedcarbon (1 g). The resulting suspension was stirred under an atmosphereof H₂ for 56 h and filtered. The filtrate was concentrated under reducedpressure to afford the title compound as a yellow solid (0.70 g, 95%),which was used without further purification.

g)(1RS,2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid. To a solution of ethyl(1RS,2RS,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate(0.10 g, 0.2 mmol) in EtOH (5 ml) was added a solution of sodiumhydroxide (0.10 g, 2.5 mmol) in H₂O (2 ml). The resulting mixture wasstirred at room temperature overnight. The mixture was acidified, andthe solid which formed was collected by filtration and dried underreduced pressure to afford the title compound as a tan solid (0.04 g,86%).

¹H NMR (CDCl₃): δ7.25 (m, 5H); 6.90 (m, 4H); 6.77 (d, 2H, J=7 Hz); 5.95(m, 2H); 4.61 (d, 2H, J=10 Hz); 3.81 (s, 3H); 3.25 (t, 2H, J=10 Hz). MS:387 [(M−H₊]. Anal. Calc. for C₂₄H₂₀O₅·⅛ H₂O: C, 73.79; H, 5.22. Found C,76.73; H 5.21.

EXAMPLE 4 (1RS, 2SR,3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid

a) Ethyl(1RS)-1-(4-Fluorophenyl)-1-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate.To a solution of ethyl3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31mmol) in THF (5 ml) under an argon atmosphere at 0° C. was added asolution of freshly prepared 4-fluorophenyl magnesium bromide (0.62mmol). After stirring for 45 min, the mixture was partitioned between 3MHCl and EtOAc. The organic extract was washed successively with H₂O, 5%aqueous NaHCO₃ and saturated aqueous NaCl. The solvent was removed invacuo, and the residue was purified by flash chromatography, elutingwith 15% EtOAc/ hexanes to afford the title compound (45 mg, 35%).

b) Ethyl(RS)-1-(4-Fluorophenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate.To a solution of ethyl(1RS)-1-(4-fluorophenyl)-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate(45 mg, 0.11 mmol) in CH₂Cl₂ (3 ml) at 0° C. was added triethylsilane(38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98mmol). The reaction mixture was allowed to warm to room temperature andstirred for 15 min, at which time was added slowly 3M HCl. The mixturewas extracted with EtOAc. The organic extract was washed successivelywith H₂O, 5% aqueous NaHCO₃ and saturated aqueous NaCl. The solvent wasremoved in vacuo to provide the title compound (40 mg, 90%) as a mixtureof Δ1 and Δ2 double bond isomers.

c) Ethyl (1RS, 2RS,3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate.To a solution of ethyl(RS)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate(40 mg, 0.10 mmol) in EtOH (3 ml) was added 10% palladium on activatedcarbon (45 mg). The resulting suspension was stirred under an atmosphereof H₂ overnight, then was filtered through a pad of Celite. The filtratewas concentrated under reduced pressure to afford the title compound (40mg, 100%), which was used without further purification.

d) (1RS, 2SR,3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid. To a solution of ethyl(1RS,2RS,3SR)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate(60 mg, 0.15 mmol) in EtOH (0.5 ml) was added 6M KOH (0.14 ml, 0.84mmol). The resulting mixture was allowed to stir at room temperatureovernight, then was concentrated under reduced pressure. The residue waspartitioned between H₂O and Et₂O. The aqueous phase was acidified with3M HCl and extracted several times with EtOAc. The combined EtOAcextracts were washed successively with H₂O and saturated aqueous NaCland dried (MgSO₄). The solvent was removed in vacuo to afford an oil,which was crystallized from EtOAc/ hexanes. The title compound wasobtained as an off-white crystalline solid (22 mg, 39%); m.p. 146-149°C.

¹H NMR (CDCl₃): δ7.23 (m, 4H); 6.96 (m, 1H); 6.90 (m, 1H); 6.79 (s, 2H);6.75 (s, 1H); 5.96 (m, 2H); 4.62 (apparent br t, 2H, J=10 Hz); 3.25 (t,1H, J =10 Hz). MS m/e (rel. int.): 753 [(2M+1)₊, 3]. Anal. Calcd. forC₂₃H₁₇FO₄: C, 73.40; H, 4.55. Found: C, 73.19; H, 4.45.

EXAMPLE 5 (1RS, 2SR,3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid

a) Ethyl(1RS)-1-Hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate.To a solution of ethyl3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31mmol) in THF (2 ml) under an argon atmosphere at 0° C. was added asolution of freshly prepared 3-methoxyphenyl magnesium bromide (0.31mmol). After stirring for 15 min, additional 3-methoxyphenyl magnesiumbromide (0.06 mmol) was added. Stirring was continued for 45 min, atwhich time thin layer chromatographic analysis indicated that thereaction was incomplete. Additional 3-methoxyphenyl magnesium bromide(0.12 mmol) was added. After stirring for 2 h more, the mixture waspartitioned between 3M HCl and EtOAc. The organic extract was washedsuccessively with H₂O, 5% aqueous NaHCO₃, H₂O and saturated aqueousNaCl. The solvent was removed in vacuo, and the residue was purified byflash chromatography, eluting with 15% EtOAc/ hexanes to afford the tidecompound (150 mg, 100%).

b) Ethyl (1RS)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate.To a solution of ethyl(1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate(150 mg, 0.35 mmol) in CH₂Cl₂ was added triethylsilane (67 μl, 0.42mmol), followed by boron trifluoride etherate (213 μl, 1.73 mmol). Thereaction mixture was allowed to stir for 30 min, at which time was addedslowly 5% aqueous HCl. The mixture was extracted with EtOAc. The organicextract was washed successively with H₂O, 5% aqueous NaHCO₃, H₂O andsaturated aqueous NaCl and dried (MgSO₄). The solvent was removed invacuo, and the residue was purified by flash chromatography, elutingwith 10% EtOAc/ hexanes to provide the title compound (45 mg, 31%) as amixture of Δ1 and Δ2 double bond isomers.

c) Ethyl (1RS, 2RS,3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate.To a solution of ethyl(RS)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate(45 mg, 0.11 mmol) in EtOH (3 ml) was added 10% palladium on activatedcarbon (45 mg). The resulting suspension was shaken on a Parrhydrogenator at 50 psi H₂ overnight, then was filtered through a pad ofCelite. The filtrate was concentrated under reduced pressure to affordthe title compound (43 mg, 94%), which was used without furtherpurification.

d)(1RS,2SR,3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid. To a solution of ethyl (1RS, 2RS, 3SR)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate(43 mg, 0.10 mmol) in EtOH (1 ml) was added 6M KOH (0.10 ml, 0.60 mmol).The resulting mixture was allowed to stir at room temperature overnight,then was partitioned between H₂O and Et₂O. The aqueous phase wasacidified with 3M HCl and extracted several times with EtOAc. Thecombined EtOAc extracts were washed successively with H₂O and saturatedaqueous NaCl and dried (MgSO₄). The solvent was removed in vacuo toafford an oil, which was crystallized from Et₂O/ hexanes. The titlecompound was obtained as a solid; m.p. 131-133° C.

¹H NMR (CDCl₃): δ7.21 (m, 3H); 6.97-6.73 (m, 8H); 5.95 (m, 2H); 4.61(apparent br t, 2H, J=9 Hz); 3.67 (s, 3H); 3.30 (t, 1H, J=9 Hz). MS m/e(rel. int.): 777 [(2M+1)⁺, 65]. Anal. Calcd. for C₂₄H₂₀O₅: C, 74.21; H,5.19. Found: C, 74.71; H, 5.47.

EXAMPLE 6 (1RS,3RS)-1,3-Di-(3,4-methylenedioxyphenyl)-indane-2-carboxylic acid

a) Ethyl(1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate.To dry magnesium turnings (0.25 g, 10 mmol) under an argon atmospherewas added a solution of 4-bromo-1,2-methylenedioxybenzene (2.1 g, 10mmol) in 1:10 THF/ Et₂O (22 ml). The resulting solution was allowed tostir at room temperature for 2 h. During this time, additional THF (4ml) was added. The resulting 3,4-methylenedioxyphenylmagnesium bromidewas added to a solution of ethyl3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.50 g, 2 mmol)in 1: 4 THF/ Et₂O (25 ml) under an argon atmosphere at 0° C. Theresulting mixture was stirred at 0° C. for 15 min, at which time 1M HCl(50 ml) was added. The phases were separated and the aqueous phase wasextracted with Et₂O. The combined organic extracts were washed withsaturated aqueous NaCl and dried (MgSO₄). The solvent was removed invacua, and the residue was purified by flash chromatography, elutingwith 10% EtOAc/ hexanes to afford the title compound as a yellow solid(0.29 g, 42%).

b) Ethyl (RS)-1,3-Di-(3,4-methylenedioxyphenyl)indene-2-carboxylate. Toa solution of ethyl(1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate(0.29 g, 0.65 mmol) in CH₂Cl₂ (3 ml) at 0° C. under an argon atmospherewas added triethylsilane (91 mg, 0.78 mmol), followed by borontrifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture wasstirred for 10 min, at which time was added ice-cold 1M HCl, and themixture was extracted with EtOAc. The organic extract was washed withsaturated aqueous NaCl and dried (MgSO₄). The solvent was removed invacuo, and the residue was placed on a small pad of silica gel, elutingwith CH₂Cl₂ to provide the title compound (257 mg, 92%).

c) Ethyl (1RS,3RS)-1,3-Di-(3,4-methylenedioxy-phenyl)indane-2-carboxylate. Ethyl(RS)-1,3-di-(3,4-Methylenedioxyphenyl)indene-2-carboxylate (163 mg, 0.38mmol) was placed in MeOH (0.05 ml), and to this was added SmI₂ (10 ml of0.1M solution in THF, 1.0 mmol). The resulting mixture was stirred underan argon atmosphere overnight, at which time thin layer chromatographicanalysis indicated that the reaction was incomplete. Additional SmI₂ (5ml of 0.1M solution in THF, 0.5 mmol) was added, and stirring wascontinued for 2 h. The reaction mixture was partitioned between Et₂O and5% aqueous Na₂S₂O₃. The organic extract was washed with saturatedaqueous NaCl and dried (MgSO₄). The solvent was removed under reducedpressure, and the residue was purified by flash chromatography, elutingwith 10% EtOAc/ hexanes to afford the title compound as a colorless,glassy solid (120 mg, 75%).

d) (1RS, 3RS)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxylic acid.To a solution of ethyl (1RS,3RS)-1,3-di-(3,4-methylenedioxyphenyl)indane-2-carboxylate (75 mg, 0.17mmol) in EtOH (20 ml) was added NaOH (0.10 g, 2.5 mmol). The resultingmixture was allowed to stir at room temperature for 3 d, at which timethin layer chromatographic analysis indicated that the reaction wasincomplete. The mixture was then heated at reflux for 36 h, allowed tocool and was concentrated under reduced pressure. To the residue wasadded concentrated HCl, and the solid which formed was collected byfiltration and dried. The solid was triturated with boiling hexanes toafford the title compound as a white solid (50 mg, 73%); m.p. 182-185°C.

¹H NMR (CDCl₃) : δ7.25 (m, 2H); 7.15 (m, 1H); 7.00 (m, 1H); 6.76 (s,2H); 6.68 (m, 2H); 6.50 (dd, 1H, J=8, 1 Hz); 6.40 (d, 1H, J=2 Hz); 5.94(s, 2H); 5.90 (d, 1H, J=1 Hz); 5.87 (d, 1H, J=1 Hz); 4.84 (d, 1H, J=10Hz); 4.78 (d, 1H, J=10 Hz); 3.63 (dd, 1H, J=10 Hz, 9 Hz). MS: 402 (M)⁺.

Anal. Calcd. for C₂₄H₁₈O₆·⅕ H₂O: C, 71.00; H, 4.52. Found: C, 71.13; H,4.46.

EXAMPLE 7 (trans,trans)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxylic acid

a) Ethyl (cis,cis)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To asolution of ethyl(RS)-1,3-di-(3,4-methylenedioxyphenyl)indene-2-carboxylate (93 mg, 0.22mmol) in EtOH (2 ml) was added 10% palladium on activated carbon (0.10g). The resulting suspension was shaken on a Parr hydrogenator at 55 psiH₂ for 2 d, then was filtered through a pad of Celite. The filtrate wasconcentrated under reduced pressure to afford the title compound (45 mg,48%) as a glassy, yellow solid, which was used without furtherpurification.

b) (trans, trans)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid. To a solution of ethyl (cis,cis)-1,3-di-(3,4-methylenedioxyphenyl)indane-2-carboxylate (45 mg, 0.1mmol) in 2: 1 EtOH/ H₂O (15 ml) was added sodium hydroxide (50 mg, 1.2mmol). The resulting solution was allowed to stir at room temperatureovernight, then was concentrated under reduced pressure. The residue wastreated with concentrated HCl, and the solid which formed was collectedby filtration and dried. The solid was recrystallized from Et₂O/ hexanesto afford the title compound as a light tan solid (12 mg, 30%); m.p.188-191° C.

EXAMPLE 8 (1RS, 2RS,3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-carboxylic acid

a) Ethyl(1RS)-1-Hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate.To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added asolution of freshly prepared 3,4-methylenedioxyphenyl magnesium bromide(5.4 mmol). After stirring for 30 min, the mixture was partitionedbetween 3M HCl and EtOAc. The organic extract was washed successivelywith H₂O, 5% aqueous NaHCO₃ and saturated aqueous NaCl and dried(MgSO₄). The solvent was removed in vacuo, and the residue was purifiedby flash chromatography, eluting with 10% EtOAc/hexanes to afford thetitle compound (1.03 g, 72%).

b) Ethyl (RS)-1-(3,4-Methylenedioxyphenyl)-3-phenylindene-2-carboxylate.To a solution of ethyl(1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate(1.03 g, 2.58 mmol) in CH₂Cl₂ (40 mL) was added triethylsilane (0.49 ml,3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol).The reaction mixture was allowed to stir for 15 min, at which time wasadded slowly 3M HCl. The mixture was extracted with EtOAc. The organicextract was washed successively with H₂O, 5% aqueous NaHCO₃ andsaturated aqueous NaCl. The solvent was removed in vacuo to provide thetitle compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bondisomers.

c) Ethyl (1RS, 2SR,3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-carboxylate. To asolution of ethyl(RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.00 g,2.60 mmol) in EtOH (25 ml) was added 10% palladium on activated carbon(30 mg). The resulting suspension was stirred under an atmosphere of H₂overnight. Thin layer chromatographic analysis indicated that thereaction was incomplete, so additional 10% palladium on activated carbon(30 mg) was added, and the mixture was shaken on a Parr hydrogenator at30 psi H₂ for 2 d. At this time, thin layer chromatographic analysisagain indicated that the reaction was incomplete. The reaction mixturewas filtered through a pad of Celite, and 10% palladium on activatedcarbon (250 mg) was added. The reaction mixture was shaken on a Parrhydrogenator at 60 psi H₂ overnight. Filtration and repetition of thelatter hydrogenation conditions led to complete consumption of startingmaterial. The reaction mixture was filtered through a pad of Celite, andthe filtrate was concentrated under reduced pressure to afford the titlecompound (650 mg, 65%), which was used without further purification.

d) (1RS, 2RS,3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-carboxylic acid. To asolution of ethyl (1RS, 2SR,3SR)-1-(3,4-methylenedioxyphenyl)-3-phenylindane-2-carboxylate (650 mg,1.68 mmol) in EtOH containing a few drops of THF was added 6M KOH (1.68ml, 10.1 mmol). The resulting mixture was allowed to stir at roomtemperature overnight, then was concentrated under reduced pressure. Theresidue was partitioned between H₂O and Et₂O. The aqueous phase wasacidified with 3M HCl and extracted several times with EtOAc. Thecombined EtOAc extracts were washed successively with H₂O and saturatedaqueous NaCl and dried (MgSO₄). The solvent was removed in vacuo toafford an oil, which was crystallized from EtOAc/ hexanes. The titlecompound was obtained as a solid (305 mg, 51%); m.p. 186-187° C.

Anal. Calcd. for C₂₃H₁₈O₄: C, 77.08; H, 5.06. Found: C, 76.60; H, 5.08.

EXAMPLE 9 (1RS, 2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-(tetrazol-5-yl)indane

a) (1RS, 2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxamide.A mixture of (1RS, 2SR,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid (250 mg, 0.64 mmol) in SOCl₂ (2.5 ml) was allowed to stir overnightunder an argon atmosphere. The reaction mixture was concentrated underreduced pressure, and the residue was dissolved in benzene (5 ml). Tothe resulting mixture under an argon atmosphere was added concentratedNH₄OH (5 ml). The solid which formed was collected by filtration, washedwith H₂O and dried in vacuo to afford the title compound (185 mg, 75%).

b) (1RS, 2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methyl-enedioxyphenyl)indane-2-carbonitrile.To ice-cold DMF (1 ml) under an argon atmosphere was added oxalylchloride (68 ml, 0.78 mmol). After stirring for 5 min at 0° C., asolution of (1RS, 2SR,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxamide(150 mg, 0.39 mmol) in DMF (2 ml) was added, and stirring was continuedfor an additional 10 min at 0° C. The reaction mixture was partitionedbetween EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc,and the combined organic extracts were washed successively with H₂O,aqueous NaHCO₃, H₂O and saturated aqueous NaCl and dried. The solventwas removed in vacuo to afford the title compound as a white solid (135mg, 94%) which was used without further purification.

c) (1RS, 2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-(tetrazol-5-yl)indane.To THF (2.5 ml) at −78° C. under an argon atmosphere was added aluminumchloride (90 mg, 0.67 mmol). After slowly warming to room temperature,sodium azide (130 mg, 2.2 mmol) was added, and the resulting mixture washeated at 70° C. for 5 min, then cooled to room temperature. To thereaction mixture was added a solution of (1RS, 2SR,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carbonitrile(125 mg, 0.34 mmol) in THF (2.5 ml). After heating at 70° C. overnight,thin layer chromatographic analysis of the reaction mixture indicatedthe presence of starting material, so additional Al(N₃)₃ was prepared asabove (1.34 mmol) in THF. To this was added the reaction mixture, andheating at 70° C. was resumed for an additional 5 h. The mixture waspartitioned between EtOAc and 3M HCl. The aqueous phase was extractedwith EtOAc, and the combined organic extracts were washed successivelywith H₂O and saturated aqueous NaCl and dried. The solvent was removedin vacua, and the residue was crystallized from EtOAc/ hexanes to affordthe title compound (78 mg, 56%). A portion of this material was furtherpurified by MPLC (LiChroprep RP-18, MeOH/H₂O=60/40) and thenrecrystallized; m.p. 155-157° C. (EtOAc/ hexanes).

¹H NMR (CDCl₃): δ7.28-7.15 (m, 4H); 7.03 - 6.95 (m, 2H); 6.87-6.84 (m,2H); 6.74 (s, 3H); 5.94 (d, 1H, J=1.2 Hz); 5.92 (d, 1H, J=1.2 Hz); 4.79(d, 1H, J=11.6 Hz); 4.73 (d, 1H, J=11.6 Hz); 3.79 (S, 3H); 3.65 (t, 1H,J=11.6 Hz). MS (m/e) : 413.2 [(M+H)⁺].

EXAMPLE 10 (1RS, 2SR,3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid

a) Ethyl(1RS)-1-Hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate.To dry magnesium turnings (81 mg, 3.4 mmol) under an argon atmospherewas added a solution of 2-bromoanisole (0.64 g, 3,4 mmol) in 5 :1 THF/Et₂O (3 ml). A portion of the resulting 2-methoxyphenyl magnesiumbromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solutionof ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg,0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. Afterstirring for 15 min, the mixture was partitioned between 3M HCl andEtOAc. The organic extract was washed successively with H₂O, 5% aqueousNaHCO₃, H₂O and saturated aqueous NaCl. The solvent was removed invacuo, and the residue was purified by flash chromatography, elutingwith 15% EtOAc/ hexanes to afford the title compound. (100 mg, 68%).

b) Ethyl(RS)-1-(2-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate.To a solution of ethyl(1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate(100 mg, 0.23 mmol) in CH₂Cl₂ (5 ml) was added triethylsilane (32 mg,0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol).The reaction mixture was allowed to warm to room temperature and stirredfor 10 min, at which time was added slowly 3M HCl. The mixture wasextracted with EtOAc. The organic extract was washed successively withH₂O, 5% aqueous NaHCO₃, H₂O and saturated aqueous NaCl and dried(MgSO₄). The solvent was removed in vacuo to provide the title compound(91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.

c) Ethyl (1RS, 2RS,3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate.To a solution of ethyl(RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate(90 mg, 0.22 mmol) in EtOH (10 ml) was added 10% palladium on activatedcarbon (90 mg). The resulting suspension was shaken on a Parrhydrogenator at 60 psi H₂ overnight, then was filtered through a pad ofCelite. The filtrate was concentrated under reduced pressure to affordthe title compound (90 mg, 100%), which was used without furtherpurification.

d) (1RS, 2SR,3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid. To a solution of ethyl (1RS, 2RS,3RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate(90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF wasadded 6M KOH (0.22 ml, 1.32 mmol). The resulting mixture was allowed tostir at room temperature overnight, then was concentrated under reducedpressure. The residue was partitioned between H₂O and Et₂O. The aqueousphase was acidified with 3M HCl and extracted with EtOAc. The EtOAcextract was washed successively with H₂O and saturated aqueous NaCl anddried (MgSO₄). The solvent was removed in vacuo to afford the titlecompound (40 mg, 49%).

¹H NMR (CDCl₃): δ7.37-6.73 (m, 1H); 5.93 (m, 2H); 5.03 (d, 1H, J=10 Hz);4.67 (d, 1H, J=10 Hz); 3.70 (s, 3H); 3.38 (t, 1H, J=10 Hz).

EXAMPLE 11 (1RS, 2SR,3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, sodium salt

a) 3-Benzyloxyacetophenone. To a mixture of sodium hydride (4.5 g of 80%mineral oil dispersion, 0.15 mol), which had been washed free of mineraloil, in DMF (25 ml) was added, dropwise with cooling, a solution of3-hydroxyacetophenone (20.5 g, 0.15 mol) in DMF (25 ml). Upon completionof the addition, the mixture was allowed to stir at room temperature for15 min, at which time was added benzyl bromide (25.6 g, 0.15 mol). Theresulting mixture was allowed to stir at room temperature overnight,then was partitioned between EtOAc and 3M HCl. The aqueous phase wasextracted with EtOAc, and the combined organic extracts were washedsuccessively with 1M NaOH, H₂O and saturated aqueous NaCl and dried. Thesolvent was removed in vacuo to afford the title compound (33 g, 97%),which was used without further purification.

b) Methyl 2-(3-Benzyloxy)benzoylacetate. To a mixture of sodium hydride(28.3 g of 80% mineral oil dispersion, 0.94 mol), which had been washedfree of mineral oil, in dimethyl carbonate (100 ml) under an argonatmosphere was added, over 30 min, a solution of 3-benzyloxyacetophenone(92.3 g, 0.41 mol) in dimethyl carbonate (150 ml). Upon completion ofthe addition, the mixture was heated at reflux for 30 min, then wascooled in an ice bath and quenched by the slow addition of 3M HCl. Themixture was partitioned between EtOAc and 3M HCl, and the aqueous phasewas extracted with EtOAc. The combined organic extracts were washedsuccessively with H₂O, aqueous NaHCO₃, H₂O and saturated aqueous NaCland dried. The solvent was removed in vacuo to afford the title compound(112.5 g, 97%).

c) Methyl2-(3-Benzyloxybenzoyl)-3-(3,4-methylenedioxy-phenyl)propenoate. Amixture containing methyl 2-(3-benzyloxy)benzoylacetate (75.0 g, 0.26mol), piperonal (43.6 g, 0.29 mol), acetic acid (3.6 ml) and piperidine(1.2 ml) in benzene (70 ml) was heated at reflux, with azeotropicremoval of H₂O. After heating at reflux for 4 h, the reaction mixturewas concentrated in vacua, and the residue was crystallized from EtOH toafford the title compound (93.5 g, 85%); m.p. 116-118° C.

d) Methyl (1RS,2SR)-5-Benzyloxy-1-(3,4-methylenedioxy-phenyl)-3-oxoindane-2-carboxylate.To trifluoroacetic acid (150 ml) at 0° C. under an argon atmosphere wasadded methyl2-(3-benzyloxybenzoyl)-3-(3,4-methylene-dioxyphenyl)propenoate (80.0 g,0.19 mol). The mixture was allowed to warm to room temperature andstirred for 30 min, at which time the mixture was concentrated underreduced pressure. The residue was dissolved in EtOAc and washedsuccessively with aqueous NaHCO₃, H₂O and saturated aqueous NaCl anddried. The solvent was removed in vacuo, and the oily residue wascrystallized from EtOAc/ hexanes to afford the title compound (51.3 g,64%); m.p. 148-150° C.

e) Methyl5-Benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxoindene-2-carboxylate. To asolution of methyl5-benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxoindane-2-carboxylate (27.3g, 65.6 mmol) in benzene (90 ml), cooled in an ice-H₂O bath, was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (15.4 g, 67.8 mmol). Theresulting mixture was stirred at 0° C. for 1 h, allowed to warm to roomtemperature for 1.5 h, and finally warmed to 40° C. for 1 h. The solidwhich formed was removed by filtration and washed with benzene. Thecombined filtrate and washings were poured into EtOAc (200 ml) andwashed successively with aqueous Na₂CO₃ (3×), H₂O (3×), 3M HCl, H₂O (3×)and saturated aqueous NaCl and dried. The solvent was removed in vacua,and the residue was crystallized from EtOAc/ hexanes to afford the titlecompound (16.4 g, 60%) as a red crystalline solid; m.p. 140-141° C.

f) Methyl(3RS)-5-Benzyloxy-3-hydroxy-3-(4-methoxy-phenyl)-1-(3,4-methylenedioxyphenyl)indene-2-carboxylate.To dry magnesium turnings (0.96 g, 40 mmol) under an argon atmospherewas added a solution of 4-bromoanisole (7.48 g, 40 mmol) in 9:1 Et₂O/THF(50 ml). The resulting 4-methoxyphenyl magnesium bromide solution wasadded portionwise to a solution of methyl5-benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxoindene-2-carboxylate (8.29g, 20 mmol) in THF (250 ml) under an argon atmosphere. Upon completionof the addition, the mixture was quenched by the addition of 3M HCl andextracted with EtOAc. The organic extract was washed successively withH₂O, aqueous NaHCO₃, H₂O and saturated aqueous NaCl. The solvent wasremoved in vacuo to afford the title compound (11.58 g, 100%), which wasused without further purification.

g) Methyl(RS)-5-Benzyloxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indene-2-carboxylate.To a solution of methyl(3RS)-5-benzyloxy-3-hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indene2-carboxylate (crude material prepared above) in CH₂Cl₂ (75 ml) under anargon atmosphere at 0° C. was added triethylsilane (3.9 ml, 23.6 mmol),followed by boron trifluoride etherate (14.7 ml, 120 mmol). The reactionmixture was stirred for 10 min at 0° C., at which time the mixture waspartitioned between 3M HCl and EtOAc. The organic extract was washedsuccessively with H₂O, aqueous NaHCO₃, H₂O and saturated aqueous NaCland dried. The solvent was removed in vacuo, and the residue waspurified by flash chromatography, eluting with a solvent gradient of25-45% Et₂O/ hexanes. The title compound (8.41 g, 83% for two steps) wasisolated as a mixture of Δ1 and Δ2 double bond isomers.

h) Methyl (1RS, 2RS,3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indane-2-carboxylate.To a degassed solution of methyl(RS)-5-benzyloxy-3-(4-methoxyphenyl)-2-(3,4-methylene-dioxyphenyl)indene-2-carboxylate(6.60 g, 13.0 mmol) in EtOAc (25 ml) and EtOH (175 ml) was added 5%palladium on activated carbon (0.6 g). The resulting suspension wasshaken on a Parr hydrogenator at 60 psi H₂ for 20 h, at which time NMRanalysis of the reaction mixture indicated that the reaction wasincomplete. The catalyst was removed by filtration through a pad ofCelite, and fresh 5% palladium on activated carbon (0.6 g) was added.The mixture was shaken on a Parr hydrogenator at 60 psi H₂ for anadditional 48 h. The catalyst was removed by filtration through a pad ofCelite, and the filtrate was concentrated under reduced pressure. Theresidue was crystallized from EtOAc/ hexanes to afford the titlecompound (4.83 g, 89%); m.p. 187-188° C.

i) (1RS, 2SR,3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, sodium salt. To a solution of methyl (1 RS, 2RS, 3SR)-5-hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxy-phenyl)indane-2-carboxylate(150 mg, 0.36 mmol) in EtOH (4 ml) was added 10% NaOH (4 ml), and theresulting mixture was allowed to stir under an argon atmosphereovernight. Water (5 ml) was added, and the mixture was concentratedunder reduced pressure. The concentrate was extracted with Et₂O, and theaqueous phase was acidified and extracted with EtOAc. The EtOAc extractwas washed successively with H₂O and saturated aqueous NaCl and dried.The solvent was removed in vacuo. The sodium salt was prepared, and aportion of this (100 mg) was purified by reverse-phase chromatography toafford the title compound (73 mg, 48%). Trituration of this materialwith EtOAc provided a white crystalline solid; m.p. 198° C. (dec).

¹H NMR (MeOH-d₄): δ7.20 (dd, 2H, J=6.8 Hz, 2.0 Hz); 6.85 (dd, 2H, J=6.8Hz, 2.0 Hz); 6.80-6.64 (m, 5H); 6.25 (s, 1H); 5.88-5.87 (m, 2H); 4.47(d, 1H, J=10 Hz); 4.43 (d, 1H, J=10 Hz); 3.76 (s, 3H); 3.03 (t, 1H, J=10Hz). MS (m/e): 427 [(M+H)⁺].

EXAMPLE 12 +(1S, 2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid

a) 3-(Prop-1-yloxy)acetophenone. To a slurry of NaH (13.84 g, 0.58 mol)in dry DMF (50 mL) at 0° C., was added a solution of3-hydroxyacetophenone (50 g, 0.37 mol). After stirring for 30 min.1-iodopropane (70 mL, 0.72 mol) was added and the mixture stirredovernight at room temperature. The mixture was diluted with dry DMF (50mL) and further NaH (2.77 g, 0.12 mol) added followed by 1-iodopropane(23 mL, 0.24 mol). After 1 h. TLC indicated that the reaction wascomplete and the product was cautiously quenched with 6M HCl andextracted with EtOAc. The EtOAc extract was washed successively withH₂O, 10% aqueous NaOH and then brine. After drying (MgSO₄), filtrationand evaporation gave the title compound (65 g, 98%) as a light yellowoil which was used without further purification. Anal. Calc. forC₁₁H₁₄O₂: C, 74.13; H, 7.89. Found: C, 73.85; H, 7.86.

b) Methyl 3-(Prop-1-yloxy)benzoylacetate. To a suspension of NaH (12 g,0.5 mol) in dry dimethyl carbonate (50 mL) was added slowly a solutionof 3-(Prop-1-yloxy)acetophenone (65 g, 0.37 mol) in dry dimethylcarbonate (100 mL). During the addition the exothermicity of thereaction caused refluxing. Following the addition the mixture wasstirred mechanically overnight and was then quenched cautiously with 3MHCl and extracted with EtOAc. The EtOAc extract was washed successivelywith H₂O, 5% aqueous NaHCO₃, H₂O and brine. After drying (MgSO₄),filtration and evaporation gave a yellow oil (82 g, quantitative) whichwas used without further purification. Anal. Calc. for C₁₃ H₁₆O₄: C,66.09; H, 6.83. Found: C, 67.25; H, 6.92.

c) Methyl3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate. Toa solution of methyl-3-(Prop-1-yloxy)benzoylacetate (10 g, 4.2 mmol) inbenzene (50 mL) was added 3,4-methylenedioxybenzaldehyde (6.36 g, 4.2mmol) followed by piperidine (0.42 mL, 0.42 mmol) and glacial aceticacid (8 drops approx.). The mixture was refluxed for 2 h. and thevolatiles removed in vacuo to give methyl(Z)-3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate(7.4 g, 48%) as an off white solid after trituration with methanol (m.p. 122-123° C). Anal. Calc. for C₂₁H₂₀O₆: C, 68.47; H, 5.47. Found: C,68.81; H, 5.49.

d) Methyl-(1RS,2SR)-1-(3,4-Methylenedioxyphenyl)-5-(prop-1-yloxy)-3-oxo-indane-2-carboxylate.Methyl3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate (7.4g, 2.0 mmol) was dissolved in trifluoroacetic acid (50 mL) at 0° C. andthe mixture stirred at room temperature for 20 min. The trifluoroaceticacid was removed in vacuo to give the title compound (6.4 g, 87%) as awhite solid after trituration with warm isopropanol m. p. 106-108° C.Anal. Calc. for C₂₁H₂₀O₆: C, 68.47; H, 5.47. Found: C, 68.12; H, 5.41.

e)Methyl-3-(3,4-Methylenedioxyphenyl)-6-(prop-1-yloxy)-1-oxo-indene-2-carboxylate.Methyl (1RS,2SR)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-3-oxo-indane-2-carboxylate(26.2 g, 71 mmol) was dissolved in toluene (250 mL) and DDQ(dichlorodicyano-quinone) (16.5 g, 71 mmol) was added. The mixture washeated at 80° C. for 2 h. then cooled, filtered and the solvent removedin vacuo. The product was purified by flash column chromatography onsilica gel (eluant: EtOAc/hexane, 20:80) to give the title compound asan orange solid (11.3 g, 44%); m.p. 125-126° C. Anal. Calc. forC₂₁H₁₈O₆: C, 68.85; H, 4.95. Found: C, 68.45; H, 4.97.

f)Methyl-(1RS)-1-hydroxy-(4-methoxy-2-methoxymethoxyphenyl)-1-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-carboxylate.To dry magnesium turnings (1.7 g, 69 mmol) under an argon atmosphere wasadded portionwise, a solution of 4-methoxy-2-methoxymethoxybromobenzene(16.8 g, 68 mmol) in 5% THF/ether (120 mL). The resulting4-methoxy-2-methoxymethoxyphenyl magnesium bromide was added to asolution ofmethyl-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)-1-oxo-indene-2-carboxylate(18.5 g, 51 mmol) in THF (400 mL) under an argon atmosphere at 0° C. Theresulting mixture was allowed to warm to room temperature and wasstirred for 10 min. The mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H₂O, aqueous NaHCO₃,H₂O and saturated aqueous NaCl and dried (Na₂SO₄). The solvent wasremoved under reduced pressure, and the residue purified by flashchromatography on silica gel (eluant: EtOAc/hexane, 10-20%) to affordthe title compound as a yellow oil (24.5 g, 91%). Anal. Calc. forC₃₀H₃₀O₉: C, 67.41; H, 5.66;. Found: C, 67.21; H, 5.66.

Serparation

Separation of (+) and (−) methyl(1RS)-1-Hydroxy-1-(4-methoxy-2-methoxymethoxyphenyl)-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-carboxylatewas done on a column of cellulose tris(3,5-dimethylphenyl carbamate)coated on silica gel (Daicel Chiralcel OD); retention time for (+) 8.8min. [α]²⁵ _(l) D=+87.5°(c=0.24, CH₃OH). Retention time for (−) 14.5min. [α]²⁵D+85.9°(c=0.21, CH₃OH) HPLC data: column Chiralcel OD (DAICEL)21.2 mm internal diameter, 250 mm length; solvent Ethanol:Hexane 60:40;flow rate 10 mL/min.; injection: 1 g of racemate; detection UV=405 nm

g)(+)Methyl-(1S,2S,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.A parr vessel was charged with (+) methyl(1RS)-1-hydroxy-3-(4-methoxy-2-methoxymethoxy-phenyl)-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-carboxylate(1 g, 1.8 mmol) dissolved in a small volume of EtOAc (25 mL) and 10%palladium on activated carbon (93 mg). The resulting solution wasstirred under an atmosphere of hydrogen for 120 hours and filtered. Thefiltrate was concentrated under reduced pressure and the productpurified by column chromatography on silica gel (eluant: EtOAc/hexane,5-10%) to give the 12(g) as a white foam (0.80 g, 83%). [α]²⁵ _(l)D=+105.4° (c=0.13, CH₃OH). Anal. Calc. for C₃₀H₃₂O₈: C, 69.22; H, 6.20.Found: C, 68.95; H, 6.11.

h) (+)Methyl-(1S,2S,3S)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.To a solution of methyl-(1S ,2S,3S)-3-(2-methoxymethyl-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(0.7 g, 1.3 mmol) in methanol (10 mL) concentrated HCl (0.1 mL) wasadded and it was then heated to reflux for 2 h. The solvent was theneliminated under vacuum and the residue was purified by columnchromatography on silica gel (eluant: EtOAc/hexane, 10-20%) to give the12(h) as a colorless glass (0.50 g, 78%). [α]²⁵ _(l) D=+116.0° (c=0.18,CH₃OH). Anal. Calc. for C₂₈H₂₈O₇·½ H₂O: C, 69.27; H, 6.02. Found: C,69.59; H, 5.99.

i)(+)Methyl-(1S,2S,3S)-3-(2-Carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.A solution of methyl-(1S,2S,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(0.1 g, 0.2 mmol) in dry DMF (2 mL) was added to NaH (6 mg, 0.24 mmol)in a small volume of dry DMF at 0 < C. The mixture was stirred at 0° C.for 15 min. and ethyl bromoacetate was then added (42 mg, 0.25 mmol).The resulting mixture was stirred at 0° C. for 1 h. The reaction wasthen quenched with dilute HCl and extracted with EtOAc. The EtOAcextract was washed with water then brine, dried (MgSO₄), filtered andevaporated. The product was purified by column chromatography on silicagel (eluant: EtOAc/hexane, 10-15%) to give the 12(i) as a glassy solid(82 mg, 68%).[α]²⁵ _(l) D=+116.0° (c=0.45, CH₃OH). Anal. Calc. forC₃₂H₃₄O₉: C, 68.32; H, 6.09. Found: C, 67.98; H, 6.09.

j) (+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid. To a solution of methyl-(1S,2S,3S)-3-(2-Carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(20 mg, 0.04 mmol) in dioxane (1 mL) was added 3 M NaOH solution (0.3mL, 1 mmol). The reaction mixture was heated to reflux for 4 h and aftercooling the solvent was eliminated in vacuo dissolved in water andacidified with 3N HCl. The resulting precipitate was collected byfiltration and dried to give a white solid (15 mg, 81%); m.p. 99-102[α]²⁵ _(l) D=+38.1° (c=0.22, CH₃OH). Anal. Calc. for C₂₉H₂₈O₉: C, 66.92;H, 5.42. Found C, 67.37; H, 5.32.

EXAMPLE 12A Preparation of 1-Bromo-4-methoxy-2-methoxymethoxybenzene.

a) 1-Bromo-2-hydroxy-4-methoxybenzene.3-Bromo-2-hydroxy-6-methoxybenzoic acid [T. de Paulis et. al. J. Med.Chem., (1985), 28, 1263-1269](5 g, 0.02 mol) was heated in quinoline(200 mL) at 160° C. for 1 h. On cooling, the product was partitionedbetween Et₂O and 3M HCl. The organic extract was washed with water andbrine then dried (MgSO₄), filtered and evaporated to give the titlecompound which was recrystallized from 5% ethyl acetate/hexane (4 g,97%); m.p. 40-42° C. Anal. Calc. for C₇H₇BrO₂: C, 41.41; H, 3,48. FoundC, 41.39; H, 3.37.

b) 1-Bromo-4-methoxy-2-methoxymethoxybenzene. To a suspension of NaH(2.5 g, 0.06 mol) in dry DMF (100 mL) at 0° C. was added solution of1-bromo-2-hydroxy-4-methoxybenzene (10.6 g, 0.05 mol). After stirring at0° C. for 30 min. bromomethyl methyl ether (7.8 g, 0.06 mmol) weredropwise added. The mixture was warmed to room temperature over 20 min.and then stirred for 2 h, it was then quenched cautiously by theaddition of cold dilute HCl and extracted with EtOAc. The EtOAc extractwas washed successively with; H₂O, 5% aqueous NaHCO₃, H₂O and finallybrine. After drying (MgSO₄) filtration and evaporation gave liquid. Theproduct was purified by distillation (85° C., 0.2 mm Hg) to give thetitle compound as a colorless oil (13.7 g, 97%).

¹H NMR (CDCl₃) δ7.40 (d, 1H, J=8.9 Hz), 6.75 (d, 1H, J=2.8 Hz), 6.46(dd, 1H, J=8.9, 2.8 Hz), 5.23 (s, 2H), 3.77 (s, 3H), 3.52 (s, 3H).

EXAMPLE 13 (1RS, 2SR, 3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxy-phenyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid,dicyclohexylamine salt

Methyl(1RS,2RS,3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate(0.14 g, 0.29 mmol) in dry DMF (1 ml) was added to NaH (9 mg, 0.38 mmol)in a small volume of dry DMF. The mixture was stirred at ambienttemperature for 20 min. then 3-bromopropan-1-ol (37 μl, 0.41 mmol) wasadded. After stirring for 1 h. the product was partitioned between 3Maqueous HCl and ethyl acetate. The organic layer was washed with waterthen brine, then dried (MgSO₄ anhyd.) filtered and evaporated to give anoil. The product was purified by column chromatography to provide methyl(1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(0.1g, 65%)(¹H-NMR indicated some epimerization had occurred at C-2).This material was used without further purification. Methyl (1RS, 2RS,3RS)-3- [2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate(0.04 g, 0.075 mmol) was dissolved in methanol (2 ml) and aqueouspotassium hydroxide added (2M, 0.22 ml, 0.44 mmol). The mixture wasstirred under reflux overnight then cooled, diluted with water,acidified with 3M aqueous hydrochloric acid and extracted with ethylacetate. The organic extract was washed with water and brine, dried(MgSO₄ anhydrous), filtered and evaporated to give an oil. The productwas purified by chromatography on silica-gel (eluant: ethylacetate/hexane/3% acetic acid) to give 12 mg of free acid which wasconverted to its dicyclohexylamine salt. m.p. 110-112° C.

EXAMPLE 14 (1RS, 2SR,3RS)-3-[2-(1-Carboxyeth-2-yloxy)-4-methoxy-phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid, bis-dicyclohexylamine salt

(1RS, 2SR,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (0.07 g, 0.13 mmol) was dissolved in dry dichloromethane (0.5 ml)and Dess-Martin periodinane (0.07 g, 0.17 mmol) added in drydichloromethane (1 ml). After 2 h. the product was partitioned betweenether and saturated aqueous sodium carbonate solution containing sodiumthiosulfate. The ether extract was washed with water then brine, dried(MgSO₄ anhydrous), filtered and evaporated to give an oil which was usedwithout purification. The crude product was dissolved in t-butanol (5ml) and to this was added a solution of sodium chlorite (18 mg, 0.2mmol) and sulfamic acid (21 mg, 0.22 mmol) in water (1.5 ml). After 1 h.stirring at ambient temperature the product was extracted into ethylacetate. The organic layer was washed with water then brine then dried(MgSO₄ anhyd.) filtered and evaporated to give an oil. The product waspurified by column chromatography on silica-gel (eluant: ethylacetate/hexane/3% acetic acid) to give 12 mg of free acid which wasconverted to its bis-dicyclohexylamine salt.

m.p. 160-162° C. MS (exact mass) M^(+.) : 534.1879 (free di-acid)(Δ=+1.1 mDa for C₃₀H₃₀O₉)

By the methods given above, the following compounds were made:

EXAMPLE 15 (1RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylic acid

m.p. 191-193° C.

Anal Calcd. for C₂₃H₁₈O₃: C, 80.68; H, 5.30.

Found: C, 80.54; H, 5.33.

EXAMPLE 16 (Trans, Trans)-1,3-Diphenylindane-2-carboxylic acid

m.p. 164-165° C.

MS (m/e): 332 [(M+NH₄)⁺].

EXAMPLE 17 (1RS, 2RS,3SR)-1-(4-Hydroxyphenyl)-3-phenylindane-2-carboxylic acid

MS (m/e): 331 [(M+H)⁺].

EXAMPLE 18 (1RS, 2RS,3SR)-1-(4-Carboxyphenyl)-3-phenylindane-2-carboxylic acid

MS (m/e): 359 [(M+H)⁺].

EXAMPLE 19 (1RS, 2RS,3SR)-1-(3-Methoxyphenyl)-3-phenylindane-2-carboxylic acid

MS (m/e): 362 [(M+NH₄)⁺].

EXAMPLE 20 (1RS, 2RS, 3SR)-1-(4-Ethylphenyl)-3-phenylindane-2-carboxylicacid

m.p. 163 -164° C.

MS (m/e): 360 [(M+NH₄)⁺].

Anal. Calcd. for C₂₄H₂₂O₂: C, 84.18; H, 6.48.

Found: C, 84.24; H, 6.73.

EXAMPLE 21 (1RS, 3RS)-1,3-Diphenylindane-2-carboxylic acid

m.p. 220-222° C (dec).(disodium salt).

EXAMPLE 22 (1RS, 2RS,3SR)-1-(4-But-4-yloxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylic acid

¹H NMR (CDCl₃): δ7.26-7.17 (m, 6H); 6.93-6.87 (m, 6H); 4.62 (d, 2H,J=10.1 Hz); 3.96 (t, 2H, J=6.5 Hz); 3.81 (s, 3H); 3.29 (t, 1H, J=10.1Hz); 1.80-1.73 (m, 2H); 1.54 - 1.45 (m, 2H); 0.98 (t, 3H, J=7.3 Hz).

EXAMPLE 23 (1RS, 2RS,3SR)-1-(4-Acetamidophenyl)-3-(4-methoxyphenyl)indane-2-carboxylic acid

m.p. 231-232° C.

MS (m/e, rel. int.): 803[(2M+1)⁺, 100].

Anal. Calcd. for C₂₅H₂₃NO₄·1/2 H₂O: C, 73.12; H, 5.85; N, 3,41. Found:C, 72.92; H, 5.61; N, 3.24.

EXAMPLE 24 (1RS, 2RS,3SR)-1-(4-Aminophenyl)-3-(4-methoxyphenyl)indane-2-carboxylic acid,dicyclohexylamine salt

m.p. 187-190° C.

MS (m/e, rel. int.): 1076.2 [(2M+1)⁺, 25].

EXAMPLE 25 (1RS, 2SR,3SR)-1-(4-Hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid

m.p. 94-96° C.

MS (m/e): 392.4 [(M+NH₄)⁺].

EXAMPLE 26 (1RS, 2RS,3SR)-1-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylic acid

m.p. 126-128° C.

MS (m/e, rel. int.): 807 [(2M+1)⁺, 35 ]; 403 [(M−H)⁻, 100].

Anal. Calcd. for C₂₅H₂₄O₅: C, 74.24; H, 5.98. Found: C, 74.10; H, 5.99.

EXAMPLE 27 (1RS, 2RS,3SR)-1-(3,4-Methylenedioxyphenyl)-3-(4-methylthioxyphenyl)indane-2-carboxylicacid

MS (exact mass): (M)⁺=404.1074 (Δ=+0.8 mDa for C₂₄H₂₀O₄S).

EXAMPLE 28 (1RS, 2SR,3SR)-5-Methoxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid

m.p. 129-131° C.

MS (m/e): 441.2 [(M+Na)⁺].

EXAMPLE 29 (1RS, 2SR,3SR)-1,3-Bis(3,4-methylenedioxyphenyl)-5-hydroxyindane-2-carboxylic acid

MS (m/e): 436.2 [(M+NH₄)⁺].

EXAMPLE 30 (1RS, 2SR,3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(2-methoxy-4,5-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid

Methyl (1RS, 2RS,3SR)-5-Hydroxy-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(2-methoxy-4,5-methylenedioxyphenyl)indane-2-carboxylicacid was prepared in 23% overall yield from methyl2-(3-benzyloxy)benzoylacetate according to the method of example 11. The5-hydroxyl moiety was then propylated according to the method given inexample 12 and this crude material treated according to the method ofexample 70 to remove the methoxymethyl group in 55% yield. The titlecompound was then obtained following the procedure given for example 12in 42% yield. m.p. 188-190° C.

Anal. Calc. for C₃₀H₃₀O₁₀: C, 65.45; H, 5.49. Found: C, 65.38; H, 5.49.

EXAMPLE 31 (1RS, 2SR,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 161-163° C.

EXAMPLE 32 (1RS, 2SR,3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

(exact mass) M^(+.) : 462.1678 (Δ=0.4 mDa for C₂₇H₂₆O₇)

EXAMPLE 33 (1RS, 2SR,3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-2-(prop-1-yloxy)-4,5-methylenedioxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylicacid

Anal. Calc. for C₃₂H₃₄O₁₀·0.5 H₂O: C, 65.41; H, 6.00. Found: C, 65.27;

H, 5.99, m.p. 196-197° C.

EXAMPLE 34 (1RS, 2SR,3RS)-1-(2-Carboxymethoxy-4,5-methylene-dioxyphenyl)-3-(4-methoxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

MS (DCI NH₃) m/e: 538.2 (M+NH₃)⁺, 520.2 (M+H)⁺(exact mass) M^(+.) :520.1733 (Δ=0.0 mDa for C₂₉H₂₈O₉)

EXAMPLE 35 (1RS, 2SR,3RS)-1-(3,4-Methylenedioxyphenyl)-3-[2-(prop-1-yloxy)phenyl]-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 179-180° C.

MS (DCI CH₄) m/e: 503.2 (M+C₂H₅)⁺, 474.1 (M+H)⁺ (exact mass) M^(+.) :474.2034 (Δ=+0.8 mDa for C₂₉H₃₀O₆)

EXAMPLE 36 (1RS, 2SR,3RS)-3-(2-Hydroxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 97-98° C.

MS (exact mass) M^(+.) : 432.1568 (Δ=+0.5 mDa for C₂₆H₂₄O₆)

EXAMPLE 37 (1 RS, 2SR,3RS)-3-(2-Carboxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 169-170° C.

Anal. Calc. for C₂₈H₂₆O₈·0.25 H₂O: C, 67.94; H, 5.40. Found: C, 67.75;H, 5.37.

EXAMPLE 38 (1RS, 2SR,3RS)-3-(2-Benzyloxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

MS (exact mass) M^(+.) : 552.2149 (Δ=−0.1 mDa for C₃₄H₃₂O₇)

EXAMPLE 39 (1RS, 2SR,3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, dicyclohexylamine salt

m.p. 182-184° C.

Anal. Calc. for C₄₁H₅₃NO₈: C, 71.59; H, 7.77; N, 2.04. Found: C, 71.67;H, 7.66; N, 2.42.

EXAMPLE 39A (+) (1S, 2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylicacid

a) Benzyloxyethylbromide

A mixture of benzyl bromide (103 g, 0.60 moles) and tetrathylammoniumiodide (3.1 g, 0.012 moles) under argon was heated to 145° C. Ethylenecarbonate (84.5 g, 0.96 moles) was added over 0.75 hr., and the reactionmixture stirred at 145-160° C. for 24 hrs. The mixture was cooled,diluted with 250 ml of deionized water and extracted with 2×200 ml ofmethylene chloride. The organic extracts were washed with brine, driedover MgSO₄, and concentrated in vacuo. Distillation gave 90 g (70%) ofproduct as a light yellow liquid (b.p. 80-85° C., 0.5 mm).

b) 1-Bromo-2-(2-benzyloxyeth-1-yloxy)-4-methoxybenzene

A mixture of 1-bromo-2-hydroxy-4-methoxy benzene (68.3 g, 0.336 moles),anhydrous potassium carbonate (51.2 g 0.37 moles) and 0.5L ofN,N-dimethylformamide was heated to 65° C. Benzyloxyethylbromide (76.0g, 0.353 moles) was added dropwise over 0.5 hr. After stirring for 1.5hr. at 65° C., the reaction mixture was cooled and filtered. Thefiltrate was diluted with 1L of deionized water, and extracted with3×0.5L ethyl acetate. The organic extracts were washed with brine, driedover MgSO₄, and concentrated in vacuo. Distillation gave 93 g (83%) ofproduct as a yellow liquid (b.p. 170-175° C., 0.5 mm).

c)Methyl(1SR)-1-hydroxy-3-[2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-propoxyindene-2-carboxylate

A solution of 1-bromo-2-(2-benzyloxyeth-1-yloxy)-4-methoxybenzene (161g, 0.478 moles) and 1.6L of tetrahydrofuran @ −70° C. under argon wastreated with n-butyl lithium (190 mL, 2.5 m, 0.478 moles), followed bymagnesium bromide etherate (132 g, 0.512 moles). After stirring for 0.5hr., a solution ofmethyl-3-(3,4-methylenedioxyphenyl)-5-propoxy-1-oxo-indene-2-carboxylate(1 17 g, 0.32 moles) in 1L of tetrahydrofuran was added over 0.5 hr. Thereaction mixture was stirred for 1 hr. at −70° C., and quenched byaddition of aqueous ammonium chloride. The mixture was extracted with3×1L of methyl t-butylether. The organic extracts were washed withbrine, dried over MgSO₄, and concentrated in vacuo to give 240 g ofcrude product. Chromatography on 1.5 Kg silica gel using a hexane:methylene chloride: ethyl acetate gradient gave 175 g (88%) of lightorange oil.

d) Methyl (1SR, 2SR,3SR)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylate

A mixture of methyl(1SR)-1-hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindene-2-carboxylate (88 g, 0.141 moles) 10% palladiumon carbon (21 g), 0.65L of absolute ethanol and 0.65L of ethylacetatewas hydrogenated at 50 psi, 55° C. for 48 hrs. The catalyst was filteredoff, and the filtrate concentrated in vacuo to give an amorphous glass.Crystallization from 350 mL of absolute ethanol gave 59.5 g (81%) ofwhite solid; m.p. 165-168° C.

Chiral Resolution

Separation of (+) and (−) methyl (1SR, 2SR,3SR)-3-[2-(2-hydroxyeth-1-yloxy)4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylatewas accomplished using an amylose tris (3,5-dimethylphenylcarbamate)coated on silica gel (Daicel Chiralpak AD). The mobile phase consistedof 50:40:10 hexane: isopropanol: chloroform. The retention times of theenantiomers were 4.7 min (+isomer), and 9.2 min (−isomer), using a4.6×250 mm column at 1.0 ml/min.

e) (+) (1S, 2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylicacid

To a solution of (+) methyl (1S, 2S,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylate(69.3 g, 0.133 moles) in 1.4L of methanol and 0.14L of deionized waterwas added 50% aqueous sodium hydroxide (0.059L, 0.74 moles). Thereaction mixture was refluxed for 16 hrs. After concentrating themixture in vacuo, the slurry was diluted with 1L of deionized water, andacidified to pH 2 with 3 N HCl. The mixture was extracted with 3×500 mLof methyl-t-butyl ether. The organic extracts were combined, washed withbrine, dried of MgSO₄, and concentrated in vacuo. The resulting oil wascrystallized from 400 mL of isopropanol to give 40.7 g (60%) of whitesolid; m.p. 119 °-122° C.; [α]_(D) ^(24° C.)=+60.4° (C=0.5, CH₃OH).

Formation of the hemiethylenediamine salt gave a white crystallinesolid; m.p. 177-179° C.; [α]_(D) ^(24° C.)+70.0° (C=0.5, CH₃OH).

EXAMPLE 40(1RS,2SR,3RS)-3-(2-Ethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylicacid

Anal. Calc. for C₂₉H₃₀O₇: C, 71.01; H, 6.16; Found: C, 70.71; H, 6.01.

EXAMPLE 41 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(prop-1-yloxy)phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

Anal. Calc. for C₃₀H₃₂O₇: C, 71.41; H, 6.39; Found: C, 71.43; H, 6.31.

EXAMPLE 42 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(prop-2-yloxy)phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 75-79° C.

EXAMPLE 43 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(2-methylprop-1-yloxy)phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 85-89° C.

EXAMPLE 44 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(3-methylbut-1-yloxy)phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, dicylohexylamine salt

m.p. 150-155° C.

EXAMPLE 45 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(3-pyridylmethoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

Anal. Calc. for C₃₃H₃₁NO₇·0.5H₂O: C, 71.02; H, 5.78; N, 2.51; Found: C,71.02; H,5-53; H, 2.30.

EXAMPLE 46 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(4-pyridylmethoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

Anal. Calc. for C₃₃H₃₁NO₇·0.5H₂O: C, 71.02; H, 5.78; N, 2.51; Found: C,70.89; H, 5.59; H, 2.37.

EXAMPLE 47 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(2-pyridylmethox)phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 153-155° C.

EXAMPLE 48(1RS,2SR,3RS)-3-[2-(Hept-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 70-73° C.

EXAMPLE 49 (1RS, 2SR,3RS)-3-[4-Methoxy-2-(5-tetrazolylmethoxy)-phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid.

m.p. 102-105° C.

EXAMPLE 50(1RS,2SR,3RS)-3-(2-Cyanomethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 199-201° C.

EXAMPLE 51(1RS,2SR,3RS)-3-(2-Carboxamidomethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

Anal. Calc. for C₂₉H₂₉NO₈·0.5C₄H₈O: C, 67.02; H, 5.99; N, 2.52; Found:C, 67.76; H, 5.96; H, 2.56.

EXAMPLE 52 (1RS, 2SR, 3SR)-5-Acetamido-1,3-bis(3,4-methylenedioxyphenyl)indane-2-carboxylicacid.

MS m/e : 460 [(M+H)⁺].

EXAMPLE 53 (1RS, 2SR,3SR)-5-Amino-1,3-bis(3,4-methylenedioxyphenyl)indane-2-carboxylate,dicyclohexylamine salt.

MS m/e: 418 [(M+H)⁺].

EXAMPLE 54(1RS,2SR,3RS)-3-[2-(3-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

a) Ethyl 3-[tri-(but-1-yl)stannyl)benzoate

Ethyl 3-bromobenzoate (2.0 g, 8.7 mmol), hexabutyl-distannane (5.51 ml,10.9 mmol), tetakis(triphenyl-phosphine)palladium(0) (0.08 g, 0.07 mmol)and palladium (II) acetate (0.19 g, 0.85 mmol) were mixed in dry toluene(25 ml) and refluxed for 72 h under argon. The solvent was removed invacuo and the residue purified by column chromatography on silica gel(eluant:hexane). The title compound was obtained as a colorless oil (1.1g, 30%).

b) Methyl (1RS,2RS,3RS)-3-[2-(3-carbomethoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate

Methyl (1RS, 2SR,3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(0.118 g, 0.19 mmol), lithium chloride (0.058 g, 1.37 mmol),tetrakis(tri-phenylphosphine)-palladium(0) (0.018 g, 0.016 mmol) andethyl 3-[tri-(butyl-1-yl)stannyl]benzoate (0.253 g, 0.58 mmol) weremixed in dry dimethylformamide (5 ml) and refluxed for 24 h. The productwas filtered through celite and the celite washed with ethyl acetate.The combined filtrate was evaporated in vacuo and was shown to be amixture of two components by TLC. Purification by column chromatographyon silica-gel gave a less polar fraction: methyl (1RS, 2SR,3SR)-3-[2-(but-1-yl)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(0.038 g) which was obtained as a colorless oil. The title compound wasthe more polar component (0.08 g) which while contaminated with tinresidues (¹H-NMR) was used without further purification.

c) (1RS, 2SR,3RS)-3-[2-(3-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid

Methyl (1RS, 2SR,3RS)-3-[2-(3-Carbomethoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(0.08 g, crude) was dissolved in propan-2-ol (1 ml) and aqueous sodiumhydroxide (1M, 1 ml ,1 mmol) added. The mixture was refluxed for 12 hr.then cooled, diluted with water, acidified with 3M-aqueous hydrochloricacid and extracted with ethyl acetate (3×). The combined organic extractwas purified by column chromatography on silical-gel (eluant: 30%EtOAc/hexane/5%AcOH) to give the title compound as a colorless solid (20mg)

m.p. 257-268° C.

EXAMPLE 55 (1RS, 2SR,3SR)-3-[2-(But-1-yl)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, dicyclohexylamine salt

Methyl (1RS, 2SR,3SR)-3-[2-(But-1-yl)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylate(0.038 g, 0.074 mmol) was dissolved in propan-2-ol (1 ml) and aqueoussodium hydroxide (1M, 0.75 ml,0.75 mmol) added. The mixture was refluxedfor 12 hr. then cooled, diluted with water, acidified with 3M-aqueoushydrochloric acid and extracted with ethyl acetate (3×). The combinedorganic extract was purified by column chromatography on silica-gel(eluant: 30% EtOAc/hexane then 30% EtOAc/hexane/5% AcOH). Conversion ofthe product to its dicyclohexylamine salt gave the title compound.

m.p. 179-182° C.

Anal. Calc. for C₄₁H₅₃NO₈: C, 71.59; H, 7.77;

N, 2.04. Found: C, 71.67; H, 7.66; N, 2.42.

EXAMPLE 56 (1RS, 2SR,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

a) Methyl (1RS, 2RS,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate

To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) andtetrakis(triphenylphosphine)-palladium(0) (24 mg, 0.02 mmol) in drydioxane (3 mL) was added a solution of Methyl (1RS, 2RS,3RS)-3-(4-Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(95 mg, 0.16 mmol) and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol)in dioxane (1 mL). The mixture was refluxed under Argon for 17 h, cooledto room temperature, diluted with ethyl acetate (5 ml) and the resultingsolution washed sequentially with brine and water. The organic layer wasdried (MgSO₄ anhydrous), filtered through a short pad of silica gel andconcentrated in vacuo to yield an oil. The product was purified by flashcolumn chromatography (silica gel, gradient elution from hexanes to 10%ethyl acetate/hexanes) to afford the title compound as a white solid.(92 mg, 86%).

b)(1RS,2SR,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid To a solution of Methyl (1RS, 2RS,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(80 mg, 0.12 mmol) in dioxane (2 mL) was added 1M aqueous NaOH (0.3 mL,0.3 mmol). The resulting mixture was heated to reflux for 48 h, thenconcentrated under reduced pressure. The residue was partitioned betweendilute aqueous HCl and ethyl acetate. The ethyl acetate extract waswashed with water and dried (MgSO₄ anhydrous). The solvent was removedin vacuo and the residue purified by flash column chromatography (silicagel, 20% ethyl acetate/hexane containing 5% of acetic acid) to affordthe title compound (36 mg, 46%).

m.p. 199-200° C.

¹H NMR (CDCl₃) δ7.18-7.09 (m, 6H); 6.85 (dd, 1H, J=8.6, 2.1 Hz);6.71-6.65 (m, 6H),6.36 (b s, 1H), 5.85 (s, 2H), 4.59 (d, 1H, J=10.2 Hz);4.31 (d, 1H, J=10.2 Hz); 3.75 (t, 2H, J=7.3 Hz); 3.73 (s, 3H); 3.14 (dd,1H, J=10.2, 10.2 Hz); 1.68 (sextet, 2H, J=7.3 Hz); 0.93 (t, 3H, J=7.3Hz).

MS m/e: 540 (M+NH₄)⁺.

Anal. Calc. for C₃₃H₃₀O₆·¾ H₂O: C, 73.93; H, 5.90. Found: C, 74.12, H,5.80.

EXAMPLE 57 (1RS, 2SR,3SR)-3-[2-[(E)-2-Carboxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylicacid

a) Methyl (1RS, 2SR,3SR)-3-[2-[(E)-2-carbomethoxy-ethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylene-dioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

1,3-bis(diphenylphosphino)propane (0.066 mmol),tris(dibenzylideneacetone)-dipalladium(0) (24 mg, 0.026) andbis(triphenylphosphine)palladium(II) choride (18 mg, 0.026 mmol), weredissolved in a 4:1 mixture of triethylamine/acetonitrile (5 mL) underargon. After 10 min at room temperature, a solution of methyl (1RS, 2SR,3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(160 mg, 0.26 mmol) and methyl acrylate (679 mg, 7.89 mmol) was added inthe above solvent mixture (3 mL). The reaction mixture was heated toreflux under argon for 20 h, cooled to room temperature and a smallaliquot analyzed by ¹H NMR, which showed no reaction had taken place.Palladium(II) acetate (6 mg, 0.025 mmol) and methyl acrylate (679 mg,7.89 mmol) in dry DMF (5 mL) were then added. The reaction mixture washeated to reflux overnight. On cooling the solution was filtered througha short column of silica gel and concentrated to yield an oil. The crudeproduct was purified by flash column chromatography ( silica gel,gradient elution: 10 % to 20% ethyl acetate/hexanes to afford the titlecompound as a tan solid. (87 mg, 62%).

¹H NMR (CDCl₃) : δ8.17 (d, 1H, J=15.7 Hz); 7.44 (d, 1H, J=8.7 Hz),7.11-7.07 (m, 2H); 6.90-6.70 (m, 6H), 6.42 (d, 1H, J=15.7 Hz); 5.94 (bs, 2H), 5.04 (d, 1H, J=7.5 Hz); 4.75 (d, 1H, J=7.6 Hz); 3.89 (t, 2H,J=6.7 Hz); 3.85 (s, 3H); 3.85 (dd, 1H, J=7.5, 7.4 Hz); 3.83 (s,3H); 2.96(s,3H), 1.79 (sextet, 2H, J=6.7 Hz); 1.03 (t, 3H, J=6.7 Hz).

b) (1RS, 2SR,3SR)-3-[2-[(E)-2-Carboxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

To a solution of methyl (1RS, 2SR,3SR)-3-[2-[(E)-2-carbomethoxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(80 mg, 0.15 mmol) in dioxane (2 ml) was added 1 N NaOH (0.5 ml, 0.5mmol). The resulting mixture was heated to reflux for 3 h, then cooledand concentrated under reduced pressure. The residue was partitionedbetween dilute aqueous HCl and ethyl acetate. The ethyl acetate extractwas washed with water and dried (MgSO₄ anhydrous). The solvent wasremoved in vacuo and the title compound was obtained as a white solid(73 mg, 96%).

¹H NMR (CDCl₃): δ8.32 (d, 1H, J=15.6 Hz); 7.24-6.55 (m, 9H); 6.29 (d,1H, J=15.6 Hz); 5.94 (b s, 2H), 5.18 (d, 1H, J=9.9 Hz); 4.69 (d, 1H,J=9.9 Hz); 3.85 (s, 3H); 3.84 (t, 2H, J=6.9 Hz); 2.94 (dd, 1H, J=9.9,9.9 Hz); 1.79 (sextet, 2H, J=6.9 Hz); 1.00 (t, 3H, J=6.9 Hz).

MS m/e : 517 [(M+H)⁺].

Anal. Calc. for C₃₀H₂₈O₈: C, 69.76; H, 5.46. Found: C, 69.73, H, 5.26.

EXAMPLE 58 (1RS, 2SR,3SR)-3-[2-(2-Carboxyeth-1-yl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid.

To a solution of (1RS, 2SR,3SR)-3-[2-[(E)-2-carboxy-ethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxy-phenyl)-5-(prop- 1 -yloxy)indane-2-carboxylic acid(43 mg, 0.08 mmol) in ethanol (5 mL) was added 10% palladium onactivated carbon (40 mg). The resulting suspension was stirred overnightunder an atmosphere of hydrogen then filtered through a pad of celite.The filtrate was concentrated under reduced pressure to afford the titlecompound (35 mg, 82%) as a white solid.

¹H NMR (CDCl₃): δ6.99 (d, 1H, J=8.6 Hz); 6.78-6.66 (m, 7H); 6.23 (b s,1H); 5.88-5.87 (m, 2 H); 4.88 (d, 1H, J=9.7 Hz); 4.54 (d, 1H, J=9.7 Hz);3.72 (s, 3H); 3.70 (t, 2H, J=7 Hz); 2.98-2.90 (m, 1H); 2.68-2.51 (m,2H); 1.65 (sextet, 2H, J=7.0 Hz); 0.89 (t, 3H, J=7.0 Hz). MS (exactmass) M^(+.) : 518.1930 (D=+1.1 mDa for C₂₇H₂₆O₇)

By the methods given above in Examples 54 to 58, the following compoundswere made.

EXAMPLE 59(1RS,2SR,3RS)-3-(2-Carboxymethylthio-4-methoxyphenyl)-1-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 242-246° C. (dec).

EXAMPLE 60 (1RS, 2SR,3SR)-3-[4-Methoxy-2-(prop-2-en-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m. p. 126-127° C. (exact mass) M^(+.) : 486.2021 (Δ=+2.1 mDa forC₃₀H₃₀O₆)

EXAMPLE 61 (1RS, 2SR,3SR)-3-[4-Methoxy-2-(prop-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 155-156° C.

Anal. Calc. for C₃₀H₃₂O₆: C, 73.75; H, 6.60. Found: C, 73.45, H, 6.43.

EXAMPLE 62 (1RS, 2SR,3RS)-3-[2-Carboxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

Anal. Calc. for C₂₈H₂₆O₈: C, 68.56; H, 5.34. Found: C, 68.61, H, 5.58.

EXAMPLE 63 (1RS, 2SR, 3SR)-3-[2-(2-Hydroxyethyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid

(exact mass) M⁺: 490.1994 (Δ=+0.3 mDa for C₂₉H₃₀O₇)

EXAMPLE 64 (1RS, 2SR, 3SR)-3-(2-Carboxymethyl-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

(exact mass) M^(+.) : 504.1788 (D=−0.4 mDa for C₂₉H₂₈O₈)

EXAMPLE 65 (1RS, 2SR, 3SR)-3-[2-(3-Hydroxyprop-1-yl)-4-methoxyphenyl]- 1-( 3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid

MS (exact mass) M^(+.) : 504.2143 (Δ=+0.5 mDa for C₃₀H₃₂O₇)

EXAMPLE 66 (1RS, 2SR, 3SR)-5-(4-Carboxyphenyl)-3-bis(3,4-methylenedioxyphenyl)1-indane-2-carboxylicacid.

m.p. 230-231° C.

EXAMPLE 67 (1RS, 2SR,3SR)-5-(4-Benzyloxyphenyl)-1,3-bis(3,4-methylenedioxyphenyl)indane-2-carboxylicacid.

m.p. 105-106° C.

EXAMPLE 68 (1RS, 2SR, 3SR)-5-(4-Hydroxyphenyl)-1,3-bis(3,4-methylenedioxyphenyl)indane-2-carboxylic acid.

MS m/e: 512 [(M+NH₄)⁺].

EXAMPLE 69 (trans,trans-1,3,5-tris(3,4-methylenedioxyphenyl)indane-2-carboxylic acid.

Anal. Calc. for C₃₁H₂₂O₈·⅝ H₂O: C, 69.76; H, 4.39. Found: C, 69.81, H,4.46.

EXAMPLE 70 (1RS,3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane.

a) (1RS,3RS)-3-[(2-Methoxymethoxy)-4-methoxyphenyl)]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane.

A solution of (1RS, 2SR,3RS)-3-[2-(methoxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (0.2 g, 0.39mmol) in dichloromethane (4ml) and pyridine (28 μl, 1.6mmol) was cooled to 0° C. under argon. To this solution was addedthionyl chloride (60 μl 0.8 mmol). The mixture was allowed to warm toambient temperature over 20 min. and the volatiles removed in vacuo. Theresidue was redissolved in toluene and evaporated in vacuo (twice). Theresidue was dissolved in dichloromethane (4 ml) and triethylamine (250μl) added. To this solution at room temperature under argon was added2-mercaptopyridine-N-oxide (120 mg, 0.8 mmol) dissolved indichloromethane (1 ml). After stirring for 20 min at room termperaturet-butylthiol (450 μl, 4 mmol) was added and the mixture irradiated for20 min (150 watt spotlight). The volatiles were removed in vacuo and theproduct partitioned between ethyl acetate and 3M-aq. HCl. The organicextract was washed with water, sat. aq. NaHCO₃ solution and finallybrine. After drying (MgSO₄ anhydrous), the product was filtered andevaporated. Purification by column chromatography gave the titlecompound (0.075 g, 41%). ¹H NMR (CDCl₃): δ7.13 (d, 1H, J=8.5 Hz); 6.83(d, 1H, J=8.3 Hz), 6.79-6.69 (m, 5H), 6.54 (dd, 1H, J=8.5, 2.5 Hz), 6.51(br s, 1H), 5.92 (br, s, 2H) 5.18 (d, 1H, J=6.7 Hz, ), 5.15 (d, 1H,J=6.7 Hz), 4.66 (dd, J=10.5, 7.6 Hz, 1H, J=6.7 Hz), 4.22 (dd, 1H,J=10.5, 7.4 Hz), 3.81 (m, 2H), 3.80 (s, 3H), 3,43 (s, 3H), 2.90-2.83 (m,1H), 2.06-1.98 (m, 1H), 1.73 (sextet, 1H, J=7.1 Hz), 0.92 (t, 3H, J=7.1Hz).

b) (1RS, 3RS )-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

To a solution of (1RS,3RS)-3-[(2-methoxymethoxy)-4-methoxyphenyl)]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(0.075 g, 0.16 mmol) in methanol (5 ml) was added 4-5 drops of 6M-HCland the mixture refluxed for 1.5 h under argon. The solvent was removedin vacuo and the product partitioned between EtOAc and water. Theorganic extract was washed with water then sat. aq. NaHCO₃ solution andfinally brine. After drying (MgSO₄ anhydrous) filtration and evaporationgave the title compound (0.064 g, 94%).

¹H NMR (CDCl₃): δ7.11 (d, 1H, J=8.4 Hz), 6.87 (d, 1H, J=7.8 Hz),6.77-6.74 (4 H, m), 6.61 (br s, 1H), 6.50 (dd, 1H, J=8.4, 2.5 Hz), 6.42(d, 1H, J=2.5 Hz), 5.94 (d, 1H J=1.2 Hz), 5.93 (d, 1H, J=1.2 Hz), 4.74(s, 1H), 4.43 (dd, 1H, J=10.4, 7.6 Hz), 4.20 (dd, 1H, J=10.7, 7.3 Hz),3.82 (t, 2H, J=6.7 Hz), 3.79 (s, 3H), 2.89-2.82 (m, 1H), 2.15-2.08 (m,1H), 1.77-1.71 (sextet, 2H, J=7.2 Hz), 0.99 (t, 3H, J=2.5 Hz). MS (exactmass) M+ Found: 418.1782 (Δ=−0.2 mDa for C₂₆H₂₆O₅).

EXAMPLE 71(1RS,2RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

To a slurry of sodium hydride (5 mg, 0.21 mmol) in dimethylformamide(0.5 ml) was added (1RS,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(0.058 g, 0.14 mmol) at ice-bath temperature under argon. After stirringfor 15 min, ethyl bromoacetate (50 μl, 0.2 mmol) was added and thesolution stirred for 1 h at room temperature. The product waspartitioned between ethyl acetate and 3M aq HCl. The organic extract waswashed with water, sat. aq. NaHCO₃ solution and finally brine. Afterdrying (MgSO₄ anhydrous) filtration and evaporation followed bychromatography gave (1RS,3RS)-3-(2-carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(0.041 g). The product was dissolved in hot ethanol (10 ml) and 1 M aq.NaOH added (1 ml). The mixture was refluxed for 1 h then cooled,acidified with 6M-aqueous HCl and extracted with ethyl acetate. Afterevaporation the residue was crystallized from ethyl acetate/hexane togive the title compound (0.035 g, 93%). m.p. 177-178° C.

¹H NMR (CDCl₃): δ7.18 (d, 1H, J=8.5 Hz), 6.87 (d, 1H, J=8.4 Hz),6.88-6.71 (4H, m), 6.56 (dd, 1H, J=8.4, 2.3 Hz), 6.53 (br. s, 1H), 6.41(d, 1H, J=2.3 Hz), 5.91 (br. s, 2H), 4.68-4.60 (m, 3H), 4.61 (dd, 1H,J=10.7, 7.2 Hz), 3.83-3.80 (m, 2H), 3.81 (s, 3H), 2.86 (dt, 1H, J=12.4,7.2 Hz), 2.10-1.98 (m, 1H), 1.73 (sextet, 2H, J=7.2 Hz), 0.98 (t, 3H,J=7.4 Hz). MS (exact mass) M+=476.1829 (Δ=⁺0.6 mDa for C₂₈H₂₈O₇).

EXAMPLES 72-120 The following compounds were prepared by the proceduresgiven above.

(1RS, 2SR, 3S R)-1-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)indane-2-carboxylic acid,m.p. 197-198° C.;

(1RS, 2SR,3SR)-1-(4-Ethoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, m.p. 169-170° C.;

(1RS, 2SR,3SR)-5-Carboxy-1,3-bis(3,4-methyl-enedioxyphenyl)indane-2-carboxylicacid, m.p. 112-115-120 C.;

(1RS, 2SR, 3SR)-3-(4-Methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-2-en-1-yloxy)indane-2-carboxylicacid. Anal. Calc. for C₂₇H₂₄O₆·⅝ H₂O: C, 71.16; H, 5.58. Found: C,71.31; H, 5.33;

(1RS, 2SR,3RS)-3-(2,4-Dimethoxyphenyl)-5-hydroxy-1-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, m.p. 110-113° C.;

(1RS, 2SR,3SR)-3-[5-(2,3-Dihydro)benzofuranyl]-5-hydroxy-1-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, m.p. 225-228° C.;

(1RS, 2SR,3RS)-5-Hydroxy-3-(3,4-methylenedioxyphenyl)-1-(2,4,6-trimethoxyphenyl)indane-2-carboxylicacid, m.p. 225-226° C.;

(1RS, 2SR,3SR)-1-[5-(2,3-Dihydro)benzofuranyl]-3-(4-methoxyphenyl)indane-2-carboxylicacid, m.p. 186-190° C.;

(1RS, 2SR, 3RS)-1-[3,4-(1,2-Ethylenedioxy)phenyl]-3-(4-5methoxyphenyl)indane-2-carboxylic acid, m.p. 178-181° C.;

(1RS, 2SR,3SR)-5-Hydroxy-3-(3,4-methylenedioxyphenyl)-1-(4-methoxyphenyl)indane-2-carboxylicacid, m.p. 124-127° C.;

(1RS, 2SR,3RS)-5-Hydroxy-3-(4-methoxyphenyl)-1-(2-methoxy-4,5-methylenedioxyphenyl)indane-2-carboxylicacid, m.p. 236-239° C.;

(1RS, 2SR,3SR)-1-(3,4-Methylenedioxyphenyl)-3-(4-methoxyphenyl)-5-(propyl-1-yloxy)indane-2-carboxylicacid, m.p. 132-133° C.;

(1RS, 2SR,3RS)-5-Methoxy-3-(4-methoxyphenyl)-1-(2-methoxy4,5-methylenedioxyphenyl)indane-2-carboxylicacid, m.p. 149-150° C.;

(1RS, 2SR,3RS)-3-[2-(2′-Carboxyphenoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p. 245-247° C.;

(1RS, 2SR,3RS)-3-[2-(2′-Carboxyphenoxy)-5-chloro-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p.. 199-201° C.;

(1RS, 2SR,3RS)-3-[2-Carboxymethoxy-4-methoxyphenyl-3-5-hydroxy-1-(3,4-methylenedioxyphenyl)indane-2-carboxylic acid, m.p. 182-185° C.

(1RS, 2SR,3RS)-5-(But-1-yloxy)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,⁴-methylenedioxyphenyl)indane-2-carboxylic acid, m.p. 211-219° C.

(1RS, 2SR, 3RS)-5-Butyl-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indane-2-carboxylic acid, .m.p 176-177° C.;

(1RS, 2SR,3RS)-3-[2-(4′-Methoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p. 147-148° C.;

(1RS, 2RS,3RS)-1-(2-Carboxymethoxy-4-methoxyphenyl]-3-(3,4-methylenedioxyphenyl)-4-(prop-1-yloxy)indane-2-carboxylicacid m.p. 201-206° C.;

(1RS, 2SR,3SR)-3-[2-(3′-Aminopropyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid. (exact mass) M^(+.) : 503.2290 (Δ=+1.8 mDa for C₃₀H₃₃O₆N);

(1RS, 2SR, 3RS)-5-Methoxy-1-(2-methoxy-3,4-methylenedioxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylicacid m.p. 148-149° C.;

(1RS, 2SR,3RS)-3-[2-(4′-Methoxy-2′-hydroxyphenyl)4-methoxyphenyl]-1-(3,⁴-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p. 199-200° C.;

(1RS, 2RS,3RS)-3-(2-Carboxymethoxy-4-isopropyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p. 183-185° C.;

(1RS, 2SR,3RS)-3-(2-Carboxymethoxy-4-ethyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p. 194-196° C.

(1RS, 2SR, 3RS)-3-(2-Carboxyethylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid,m.p. 148-149° C.;

(1RS, 2SR,3RS)-3-[2-[(3-Carboxypyridin-2-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid m.p. 152-155° C.

(1RS, 2SR,3RS)-3-[2-[Carbo(N,N-diethylcarbamoyl)methoxy]methoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p. 181-182° C.;

(1RS, 2SR,3RS)-1-(3,4-Methylenedioxyphenyl)-3-[4methoxy-2-(2-propen-1-yloxy)phenyl]-5-(prop-1-yloxy)indane-2-carboxylicacid, m.p. 168-170° C.;

(1RS,3RS)-3-[2-(3′-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indanedicyclohexylamine salt, m.p. 230-232° C.;

(1RS, 2SR, 3SR)- 1,3,5-Tris(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, Anal. Calc. for C₃₁H₂₂O₈·⅝ H₂O: C, 69.76; H, 4.39. Found: C,69.81, H, 4.46;

(1RS, 2SR,3RS)-1-[2-(3-Hydroxyprop-1-yloxy)-4,5-methylenedioxyphenyl)-3-(4-methoxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatedicyclohexylamine salt,

(1RS, 2SR,3RS)-1-(2-Methoxy-4,5-methylenedioxyphenyl)-3-(4-methoxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatedicyclohexylamine salt, m.p. 120-122° C.;

(1RS, 2SR,3RS)-5-Methoxy-1-(4-methoxy-2,3-methylenedioxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylatedicyclohexylamine salt, m.p. 187-188° C.;

(1RS, 2SR,3RS)-5-(3-Buten-1-yloxy)-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, m.p. 127-129° C.;

(1RS, 2SR,3RS)-5-(But-1-yloxy)-3-(1-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indane-2-carboxylicacid, m.p. 157-158° C.;

(1RS, 2RS,3SR)-5-Hydroxy-1-(3,4-methylenedioxyphenyl)-3-(4-trifluoromethoxyphenyl)indane-2-carboxylicacid; m.p. 100-104° C.;

(1RS, 2SR,3RS)-5-Hydroxy-1-(3-indolyl)-3-(4-methoxyphenyl)indane-2-carboxylicacid, m.p. 138-140° C.;

(1RS, 2SR,3SR)-5-Hydroxy-1-(5-indolyl)-3-(4-methoxyphenyl)indane-2-carboxylatedicyclohexylamine salt, m.p. 235-240° C.;

(1RS, 2S R,3SR)-3-(4-Methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-methylthioindane-2-carboxylicacid; Anal. Calc. for C₂₅H₂₂O₅·½ H₂O: C, 67.70; H, 5.23. Found: C,67.60; H, 5.40;

(1RS, 2RS,3SR)-5,6-(Methylenedioxy)-1-(3,4-methylenedioxyphenyl)-3-(4-trifluoromethoxyphenyl)indane-2-carboxylicacid, m.p. 170-172° C.;

(1RS , 2SR, 3SR)-4-Benzyl-1,3-bis(4-methoxyphenyl)indane-2-carboxylate,dicyclohexylamine salt; m.p. 160-162° C.;

(1RS, 2SR,3SR)-4-Benzyl-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate,dicyclohexylamine salt; m.p. 159-160° C.;

Trans, Trans-1,3-Bis(4-methoxyphenyl)indane-2-carboxamide, m.p. 223-225°C.;

(1RS, 2SR, 3SR)-5-Benzyloxy-1,3-bis(3,4-methylenedioxyphenyl)indane-2carboxylic acid, m.p. 191-193° C.;

(1RS, 2SR, 3SR)-3-[4-Methoxy-2-[2-(methylphosphinyl)eth-1-yl]phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatedisodium salt; (exact mass) M⁺+Na: 619.1462 (Δ=−1.2 mDa forC₃₀H₃₁O₈PNa₃)

(1RS, 2SR, 3RS, 1RS,SR)-3-[2-[1′-carboxyeth-1′-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxylphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid

(1RS, 2SR,3SR)-3-(4-Methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-methylsulfoxylindane-2-carboxylicacid;

EXAMPLE 121 (1RS, 2SR,3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatedisodium salt,

a) Methyl (1RS, 2SR,3RS)-3-[2-[(4-Formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate

To a solution of Methyl (1RS, 2SR,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (300 mg, 0.63 mmol) in DMF (4 mL) was added K₂CO₃(109 mg, 0.79 mmol) and 3-fluoro-4-formylpyridine (150 mg, 1.2 mmol).The reaction mixture was heated to reflux under Argon for 2 h. Aftercooling to room temperature it was partitioned between 3N HCl and ethylacetate. The ethyl acetate extract was washed with water, aqueous NaHCO₃and brine and dried (Mg₂SO₄). The solvent was removed in vacuo. Theresidue was purified by flash column chromatography (silica gel,gradient elution from 10% to 20% ethyl acetate/hexanes) to afford thetitle compound (128 mg, 42%).

b) Methyl (1RS, 2SR3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate

To a solution of Methyl (1RS, 2SR,3RS)-3-[2-[(4-formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (128 mg, 0.24 mmol) in t-BuOH (10 mL) was added asolution of NaClO₂ (34 mg, 0.28 mmol) and NH₂SO₃H (40 mg, 0.42 mmol) inwater (6 mL). The reaction mixture was stirred at room temperature for 2h and it was partitioned between water and ethyl acetate. The ethylacetate extract was washed with water and brine and dried (Mg₂SO₄). Thesolvent was removed in vacuo. The residue was purified by flash columnchromatography (silica gel, 25% ethyl acetate/hexanes containing 5% ofacetic acid) to afford the title compound (90 mg, 69%).

c) (1RS, 2SR,3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate disodium salt

To a solution of Methyl (1RS, 2SR,3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (90, 0.15 mmol) in isopropanol (2 mL) was added 1Maqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was heated toreflux for 12 h, then concentrated under reduced pressure. The residuewas partitioned between dilute HCl and ethyl acetate. The ethyl acetateextract was washed with water and dried (Mg₂SO₄). The solvent wasremoved in vacuao. The residue was purified by flash columnchromatography (silica gel, 30% ethyl acetate/hexanes containing 5% ofacetic acid) to afford the title compound (65 mg, 74%); m.p. 220-222° C.(dec.) (disodium salt).

EXAMPLE 122 2.2-Dimethylpropanoyloxymethyl(1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylatesodium salt

a) 2.2-Dimethylpropanoyloxymethyl(1RS,2SR,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate

(1RS, 2SR, 3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid potassium salt (125 mg, 0.54 mmol) (obtained from the treatment ofthe corresponding acid with KHCO₃ (54 mg, 0.54 mmol)) was dissolved inDMF (3 ml) and then pivaloyloxymethyl iodide (0.54 mmol) (prepared frompivaloyloxymethyl chloride (73 mg, 0.54 mmol) and excess sodium iodidein acetone) was added. The reaction mixture was stirred overnight andthen partitioned between dil. HCl and ethyl acetate. The organic layerwas washed with water and brine then dried (MgSO₄ anhyd.) filtered andevaporated. The product was purified by column chromatography to provide122(a) (120 mg, 77%) as a colorless oil.

b) 2,2-Dimethylpropanoyloxymethyl (1RS, 2SR,3RS)-3-(2-benzyloxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

2,2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate(280 mg, 0.5 mmol) in dry DMF (3 ml) was added to NaH (18 mg, 0.6 mmol)in a small volume of dry DMF. The mixture was stirred at RT for 20 min.then benzyl bromoacetate (137 mg, 0.6 mmol) was added. After stirringfor 1.5 h the product was partitioned between 3M aqueous HCl and ethylacetate. The organic layer was washed with water then brine, then driedMgSO₄ anhyd.) filtered and evaporated to give an oil. The product waspurified by column chromatography to provide 122 (b) (240 mg, 66%) as acolorless oil.

c) 2.2-Dimethylpropanoyloxymethyl(1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid.

2,2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-benzyloxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate(240 mg, 0.3 mmol) was dissolved in a 2:1 mixture of ethyl acetate andethanol (3 ml) and then 50 mg of Pd/C was added. The mixture was stirredat room temperature under a H₂ atmosphere for 3 h. The catalyst was thenfiltered, the solvent concentrated in vacuo and the resultant oilpurified by flash column chromatography. The title compound was obtained(180 mg, 86%) as a colorless oil.

MS (exact mass) (M+Na)^(+.) : 647.2335 (sodium salt)

(D=−2.3. mDa for C₃₃H₃₈O₁₁Na)

mp 190-195° C. (dec, sodium salt)

EXAMPLE 123

(1S, 2R,3S)-3-[2-[Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy)eth-1-yloxymethoxyl-4-methoxyphenyl-1-(3,4-methlenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylatesodium salt

a) Allyl (1S, 2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

(1S, 2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (4.8 g, 9.5 mmol) was dissolved in dry acetonitrile (30 ml) and DBU(1.7 ml, 11.4 mmol) was added followed by allyl bromide (3,4 g, 28.mmol). After stirring for 0.5 h. the product was partitioned between 3Maqueous HCl and ethyl acetate. The organic layer was washed with waterand brine, then dried (MgSO₄ anhyd.) filtered and evaporated to give anoil. The product was purified by column chromatography to provide thetitle compound as a pale yellow oil (5.7 g, quantitative).

b) Allyl (1S, 2R,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

Allyl (1S, 2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(1.7 g, 3.11 mmol) was dissolved in allyl alcohol (20 ml) and then 15drops of conc. HCl was added. The resulting solution was stirred at 65°C. for 2 h. After removing the solvent the residue was partitionedbetween water and ethyl acetate. The organic layers were washed withwater, 5% aqueous NaHCO₃ and brine; then dried (MgSO₄ anhyd.), filteredand evaporated to give an oil. The product was purified by columnchromatography to provide the title compound as a pale yellow oil (1.26g, 81%).

c) Allyl (1S, 2R,3S)-3-(2-Carbo-1-tert-butoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

Allyl (1S, 2R,3S)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(1.0 g, 2 mmol) in dry DMF (4 ml) was added to NaH (57 mg, 2.4 mmol) ina small volume of dry DMF. The mixture was stirred at RT for 20 min.,then tert-butyl bromoacetate (974 mg, 5 mmol) was added. After stirringfor 0.5 h., the product was partitioned between 3M aqueous HCl and ethylacetate. The organic layer was washed with water, brine and dried (MgSO₄anhyd.), filtered and evaporated to give an oil. The product waspurified by column chromatography to provide the title compound (1.1 g,93%) as a pale yellow oil.

d) Allyl (1S, 2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

Allyl (1S, 2R,3S)-3-(2-carbo-tert-butoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(765 mg, 1.24 mmol) was dissolved in TFA (5 ml) containing a few dropsof anisole. The reaction mixture was stirred at RT for 20 min. Thesolvent was eliminated, the residue was diluted with ethyl acetate,washed with water, brine and dried (MgSO₄ anhyd.), filtered andevaporated. The product was purified by column chromatography to providethe title compound (575 mg, 83%) as a colorless oil.

e) Allyl (1S, 2R,3S)-3-[2-[Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy)eth-1-yloxymethoxy]-4-methoxyphenyl-1-(3,4-methlenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylicacid sodium salt

Allyl (1S, 2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(287 mg, 0.5 mmol) was dissolved in DMF (5 ml) and Cs₂CO₃ (333 mg, 1mmol) added followed by (1S)-1-bromoethyl 2-methoxy-2-methylpropionate(225 mg, 1 mmol). The reaction mixture was stirred at RT overnight, thenpartitioned between water and ethyl acetate, washed with dil. HCl andbrine, dried (MgSO₄ anhyd.), filtered and evaporated to give an oil. Theproduct was purified by column chromatography to provide the titlecompound (260 mg, 74%) as a colorless oil.

f) (1S, 2R,3S)-3-[2-Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy)eth-1-yloxymethoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylicacid sodium salt

Allyl(1S,2R,3S)-3-[2-Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxyeth-1-yloxymethoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(260 mg, 0.37 mmol) was dissolved in CH₂Cl₂ (2 ml) andtetrakis(triphenylphosphine)palladium(0) (36 mg, 0.037 mmol) addedfollowed by tri-n-butyltin hydride (0.11 ml, 0.4 mol). The reactionmixture was stirred at RT for 3 h then quenched with 3N HCl and stirredfor 20 min. The organic layer was diluted with ethyl acetate washed withwater then brine, dried (MgSO₄ anhyd.), filtered and evaporated to givean oil. The product was purified by column chromatography to provide thetitle compound (210 mg, 85 %) as a colorless oil.

MS (exact mass) (M+Na)^(+.) : 687.2415 (sodium salt)

(D=+0.3. mDa for C₃₆H₄₀O₁₂Na)

EXAMPLE 124 (1RS, 2SR,3RS)-2-Amino-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane

(1RS, 2SR,3RS)-3-(2-tert--butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in drybenzene (4 ml) and heated at 40° C. for 2 h and at 75° C. for 2 h. Thereaction mixture was then partitioned between 1N HCl and ethyl acetate.The organic layer was washed with water and brine, dried (MgSO₄ anhyd.),filtered and evaporated to give the corresponding isocianate as acolorless oil. After purification by column chromatography (silica gel,ethyl acetate/hexane 30:70), the isocianate (100 mg) thus obtained wasdissolved in 1M HCl in dioxane (3 mL) and the mixture was heated at 80°C. overnight. The solvent was removed in vacuo, the residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄) and concentrated to give a colorlessoil that was purified by HPLC (1:1 CNCH₃:H2O(containing 0.1% TFA)) toproduce the desired product (40 mg, 42%) as an off-white solid, m.p.181-182° C. (dec).

EXAMPLE 125 (1RS, 2SR, 3RS)-2-Aminomethyl-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane

a) (1RS, 2SR,3RS)-2-Hydroxymethyl-3-(2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

(1RS, 2SR,3RS)-2-Hydroxymethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(634 mg, 1.43 mmol) was dissolved in dry acetone (15 ml) then K₂CO₃(1.97 g, 14.3 mmol) and tert-butyl bromoacetate (416 mg, 2.14 mmol) wasadded. The reaction mixture was stirred overnight. The solvent was theneliminated the residue partitioned between water and ethyl acetate. Theorganic layer was washed with dilute HCl, water, brine and dried (MgSO₄anhyd.) filtered and evaporated to give an oil. The product was purifiedby column chromatography to provide 125(a) (792 g, 98%) as a pale yellowoil.

b) (1RS, 2SR,3RS)-2-Azidomethyl-3-(2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

(1RS, 2SR,3RS)-2-Hydroxymethyl-3-(2-2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(792 mg, 1.41 mmol) was dissolved in CH₂Cl₂ (10 ml) cooled at 0° C.,triethylamine (485 mg, 4.8 mmol) and methanesulfonyl chloride (229 mg, 2mmol) were then added. The reaction mixture was kept at 0° C. for 0.5 hand then partitioned between water and ethyl acetate. The organic layerwas washed with dilute HCl, water, brine and dried (MgSO₄ anhyd.)filtered and evaporated to produce the desired mesylate (680 mg, 78%).Without further purification, the mesylate was dissolved in dry DMF (5ml), and NaN₃ was added. The reaction mixture was stirred overnight at60° C. and, after cooling to RT, it was partitioned between water andethyl acetate. The organic layer was washed with dilute HCl, water,brine and dried (MgSO₄ anhyd.) filtered and evaporated. The residue waspurified by column chromatography to produce the desired azide as acolorless oil (484 mg, 75%).

c) 1RS, 2SR,3RS)-2-Aminomethyl-3-(2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

(1RS, 2SR,3RS)-2-Azidomethyl-3-(2-2-tert-butoxycarbonylmethoxy4-methoxyphenyl) 1 -(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (484 mg, 0.78 mmol)was dissolved in ethanol (12 ml) and ethyl acetate (3 ml) and then 80 mgof 10% Pd/C were added. The reaction mixture was stirred under H₂atmosphere for 4 h. The catalyst was filtered, the solvent eliminatedand the residue purified by column chromatography (ethyl acetate/hexane25/75 followed by methanol) to obtained the desired amine (320 mg, 66%)as a colorless oil.

d) (1RS, 2SR,3RS)-2-Aminomethyl-3-(2-carboxymethoxy-4-methoxyphyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

(1RS, 2SR,3RS)-2-Aminomethyl-3-(2-2-tert-butoxycarbonylmethoxy4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(765 mg, 1.24 mmol) was dissolved in TFA (5 ml) containing a few dropsof anisole. The reaction mixture was stirred at RT for 20 min. Thesolvent was eliminated the residue was diluted with ethyl acetate washedwith water, brine and dried (MgSO₄ anhyd.), filtered and evaporated. Theproduct was purified by column chromatography to provide the titlecompound (575 mg, 83%) as a white powder m.p. 237-242° C.

EXAMPLES 126-153 Indan-5-yl-(1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylicacid sodium salt.

m.p. 181-183° C. dec.

3.5-Dimethoxyphenyl-(1RS, 2SR, 3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylateacid sodium salt

m.p. 185-189° C. dec.

(1RS)-1-(2-Methoxy-2-methylpropionyloxy)eth-1-yl (1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt

m.p. 178-181° C. dec.

N,N-Dimethylcarbamoylmethyl (1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-loxy)indane-2-carboxylatesodium salt

m.p. 170-174° C. dec.

Ethoxycarboxyloxymethyl (1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt

MS (exact mass) (M+Na)⁺: 645.1959 (sodium salt) (D=−1.1 mDa forC₃₃H₃₄O₁₂Na)

Benzoyloxymethyl (1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt

MS m/e 672 (M+NH₄)⁺

Cyclohexyloxycarboxyloxymethyl (1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt

MS (exact mass) (M+Na)^(+.) : 699.2453 (sodium salt) (D=−3.5. mDa forC₃₇H₄₀O₁₂Na)

Ethyl (1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt

MS (exact mass) M⁺: 548.2040 (free acid) (D=+0.6. mDa for C₃₁H₃₂O₉)

(1S, 2R,3S)-3-[(2-Carboxy-(2′,6′-dimethylphenyl)methoxyl-4-methoxyphenyl]-1(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium

MS (exact mass) (M+Na)^(+.) : 647.2264 (sodium salt) D=−0.7. mDa forC₃₇H₃₆O₉Na)

(1S,2R,3S)-3-[[(2-Carboxycyclopentylmethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl-5-(prop-1-yloxy)indane-2-carboxylatesodium salt

MS (exact mass) (M+Na)^(+.) : 611.2282 (sodium salt) (D=−2.5. mDa forC₃₄H₃₆O₉Na)

(1S,2R,3S)-3-[2-[Carbo(indan-5-yloxy)methoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylicacid sodium salt

MS (exact mass) (M+Na)^(+.) : 659.2281 (sodium salt) (D=−2.4. mDa forC₃₈H₃₆O₉Na)

(1S,2R,3S)-3-[2-Carbo(eth-1-yloxy)methoxyl-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

MS (exact mass) (M+2Na-H)^(+.) : 593.1769 (sodium salt) (D=−0.6 mDa forC₃₁H₃₁O₉Na₂)

(1RS,2SR,3RS)-3-(2-Carboxyethylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 148-149° C.

(1RS,2SR,3RS)-3-[2-[2-[2-Diethylamino)-2-oxoethoxy]-2-oxoethoxy]-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid

m.p. 181-182° C.

(1RS, 2SR,3RS)-2-Trifluoromethylsulfonamidomethyl-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

m.p. 184-186° C.

(1RS, 2SR,3RS)-2-Aminoethyl-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane

m.p. 207-211° C.

Indan-5-yl (1S, 2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt

Cyclopentyl (1S, 2R,3S)-3-2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt.

Ethoxycarboxymethyl (1S, 2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt.

(1RS)-1-(1-Methylethoxycarboxy)eth-1-yl (1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt.

m.p 151-155° C.

Ethyl (1S, 2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatesodium salt (1S, 2R,3S)-3-[2-Carbomethoxymethoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

(1S, 2R,3S)-3-[2-Carbobenzoyloxymethoxymethoxyl-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

(1S, 2R,3S)-3-[2-(Carboethoxycarboxyloxymethoxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

(1S, 2R,3S)-3-[2-(Carboacetoxymethoxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

(1S, 2R,3S)-3-[2-[Carbophthalidylmethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

(1S, 2R,3S)-3-[2-Carbo-(2-methoxy-2-methylpropionyloxymethoxymethoxyl-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

EXAMPLE 153

(1S,2R,3S)-3-[2-Carbo-(2,2-dimethylpropanoyloxymethoxymethoxyl-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid sodium salt

To a solution of (1S, 2R,3S)-3-[2-Carboxymethoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid monopotassium salt (170 mg, 0.3 mmol) (obtained by treatment of thecorresponding diacid (156 mg, 0.3 mmol) with 1 equiv. of KHCO₃ (30 mg,0.3 mmol)) in DMF (4 mL) pivaloyloxymethyl iodide (74 mg, 0.3 mmol) wasadded. The reaction mixture was stirred at RT for 0.5 h and morepivaloyloxymethyl iodide was then added (20 mg. 0.08 mmol) and thenstirred for an additional 0.5 h. The reaction mixture was partitionedbetween dilute aqueous HCl and ethyl acetate. The ethyl acetate extractwas washed with water and brine and dried (MgSO₄ anhydrous). The solventwas removed in vacuo and the residue was purified by flash columnchromatography (silica gel, Ethyl Acetate/hexane/HOAc 30/65/5) to obtainthe desired compound as a white foam (140 mg, 73%) as the free acidwhich was converted to its sodium salt. m.p. 128-133° C. MS (exact mass)M⁺+Na: 679.2116 (sodium salt) (D=+1.2 mDa for C₃₅H₃₇O₁₁Na₂)

EXAMPLE 154 (1RS, 2SR,3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methtlenedioxyphenyl)-5-(prop-1-yloxy)indan-2-ylacetic acid

a) (1RS, 2SR,3RS)-3-(4-Methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid. A solution of methyl (1RS, 2RS,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(2.42 g, 4.6 mmol) in isopropyl alcohol (30 ml) with aqueous NaOH (8 mlof 5 N solution) was refluxed for 4 h. The resultant mixture waspartitioned between EtOAc and 3N HCl. The organic extract was washedwith H₂O then brine, dried (Na₂SO₄) and solvent removed in vacuo toafford the title compound as a colorless oil (1.98 g, 84%).

b) Methyl (1RS, 2SR,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.To a solution of(1RS, 2SR,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (1.98 g, 3.91 mmol) in acetonitrile (15 ml) was added DBU (0.655 g,4.3 mmol) followed by iodomethane (2.77 g, 19.5 mmol). The reactionmixture was stirred at room temperature 3.5 h then partitioned betweenEtOAc and 3N HCl. The organic extract was washed with H₂O, saturatedNaHCO₃ solution, H₂O, then brine, dried (Na₂SO₄) and solvent removed invacua to provide the title compound (1.79 g, 88%) as an oil.

c) (1RS, 2RS,3RS)-2-Hydroxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane.To a solution of methyl (1RS, 2SR,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (4.45 g, 8.5 mmol) in THF (35 ml)stirred at 0° C. was added lithium aluminum hydride (17 ml of a 1Msolution in THF). The cooling bath was removed and stirring continuedfor 18 h. The reaction was quenched by addition of saturated aqueousammonium chloride solution then partitioned between EtOAc and 3N HCl.The organic extract was washed with H₂O, saturated NaHCO₃ solution, H₂O,then brine, dried (Na₂SO₄) and solvent removed in vacuo to afford thetide compound as an oil (4.13 g, 98%).

d) (1RS, 2RS,3RS)-2-Methanesulfonyloxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methlenedioxyphenyl)-5-(prop-1-yloxy)indane.To a solution of (1RS, 2RS,3RS)-2-hydroxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (1.388 g, 2.82 mmol) inmethylene chloride (10 ml) with TEA (1.2 ml) stirred under argon at 0°C. was added methanesulfonyl chloride (0.41 g, 3.5mmol). The coolingbath was removed and stirring continued for 1 h. The mixture waspartitioned between EtOAc and 3N HCl. The organic extract was washedwith H₂O, saturated NaHCO₃ solution, H₂O, then brine, dried (Na₂SO₄) andsolvent removed in vacuo to afford the title compound as an oil (1.52 g,95%).

e) 1RS, 2RS,3RS)-2-Cyanomethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane.(1RS, 2RS,3RS)-2-Methanesulfonyloxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(1.5 g, 2.96 mmol) was stirred in DMF (10 ml) under argon with NaCN(1.45 g, 29.6 mmol) at 60° C. for 20 h then cooled and partitionedbetween EtOAc and 3N HCl. The organic extract was washed with H₂O,saturated NaHCO₃ solution, H₂O, then brine, dried (Na₂SO₄) and solventremoved in vacuo to afford the title compound as an oil (1.27 g, 86%).

f) 1RS, 2RS,3RS)-2-Cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane.1RS, 2RS,3RS)-2-Cyanomethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(300 mg, 0.60 mmol) was dissolved in EtOH (4 ml) with concentrated HCl(0.1 ml) then refluxed for 1 h. the mixture was cooled then partitionedbetween EtOAc and 3N HCl. The organic extract was washed with H₂O,saturated NaHCO₃ solution, H₂O, then brine, dried (Na₂SO₄) and solventremoved in vacuo to afford the title compound as a solid foam (250 mg,91%).

g) 1RS, 2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane.To a solution of 1RS, 2RS,3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(250 mg, 0.55 mmol) in DMF (4 ml) stirred at 0° C. under argon added NaH(21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at 0° C.for 15 min then t-butylbromoacetate (107 mg, 0.55 mmol) was added. Thecooling bath was removed and the mixture was stirred for 3 h at roomtemperature then partitioned between EtOAc and 3N HCl. The organicextract was washed with H₂O, saturated NaHCO₃ solution, H₂O, then brine,dried (Na₂SO₄) and solvent removed in vacuo. The residue was purified byflash chromatography on silica gel, (eluent 25-50% Et₂O/hexanes) toafford the title compound as an oil (247 mg, 79%).

h) 1RS, 2RS,3RS)-1-(2-Carboxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane.1RS, 2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-propoxyindane(240 mg, 0.42 mmol) was stirred in methylene chloride (3 ml) with TFA(0.8 ml) under argon at room temperature for 1 h then partitionedbetween EtOAc and 3N HCl. The organic extract was washed with H₂O thenbrine, dried (Na₂SO₄) and solvent removed in vacuo to afford the productas an oil (190 mg, 88%).

i) (1RS, 2SR,3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-ylaceticacid. To a solution of 1RS, 2RS,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane(290 mg, 0.56 mmol) in methanol (ca. 1 ml) was added aqueous 2 N NaOHsolution (0.3 ml) followed by H₂O (8 ml) then (with caution) Na₂O₂ (120mg). The mixture was heated to 70° C. and stirred for 20 h at which timeHPLC showed only 15% hydrolysis. The mixture was stirred at 85° C. for 3days with 3 (100 mg) portions of Na₂O₂ added each day, the reactionmixture was partitioned between EtOAc and 3N HCl. The organic extractwas washed with H₂O then brine, dried (Na₂SO₄) and solvent removed invacuo to afford the product as an oil (228 mg, 90% pure by HPLC) Finalpurification was obtained by crystallization as the bis cyclohexylaminesalt.

mp 210-212° C.

EXAMPLE 155

Following the procedure outlined on Example 154 the following compoundwas made:(1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-yl-aceticacid. m.p. 139-146 °

EXAMPLE 156

Formulations for pharmaceutical use incorporating compounds of thepresent invention can be prepared in various forms and with numerousexcipients. Examples of such formulations are given below.

Inhalant Formulation

A compound of Formula 1, (1 mg to 100 mg) is aerosolized from a metereddose inhaler to deliver the desired amount of drug per use.

Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of Form.I) 2. Corn Starch 20 mg 3. Alginic acid 20 mg 4. Sodium Alginate 20 mg5. Mg stearate 1.3 mg  2.3 mg 

Procedure for tablets:

Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitablemixer/blender.

Step 2 Add sufficient water portion-wise to the blend from Step 1 withcareful mixing after each addition. Such additions of water and mixinguntil the mass is of a consistency to permit its conversion to wetgranules.

Step 3 The wet mass is converted to granules by passing it through anoscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4 The wet granules are then dried in an oven at 140° F. (60° C.)until dry.

Step 5 The dry granules are lubricated with ingredient No. 5.

Step 6 The lubricated granules are compressed on a suitable tabletpress.

Parenteral Formulation

A pharmaceutical composition for parenteral administration is preparedby dissolving an appropriate amount of a compound of formula I inpolyethylene glycol with heating. This solution is then diluted withwater for injections Ph Eur. (to 100 ml). The solution is then steriledby filtration through a 0.22 micron membrane filter and sealed insterile containers.

What is claimed is:
 1. A pharmaceutical composition comprising acompound of Formula (I):

wherein: R₁ is —X(CH₂)_(n)Ar, dihydrobenzofuranyl, benzodioxanyl,cyclohexyl or C₁₋₄ alkyl, wherein Ar is a moiety of formula (a) or (b);R₂ is a moiety of formula (a) or (b); P₁ is —X(CH₂)_(n)R₈; P₂ ishydrogen or C₁₋₄ alkyl; R₆ is independently hydrogen or C₁₋₄ alkyl; R₇is indenpendently hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl,all of which may be unsubtituted or substituted by one or more OH,N(R₆)₂, CO₂ R₁₂, Br, Cl, F, I, or XC₁₋₅ alkyl; or R₇ is (CH₂)_(n)Ar; R₈is hydrogen, R₁₁, CO₂ R₇, CO₂ C(R₁₁)₂ O(CO)XR₇, PO₃ (R₇)₂, SO₂ NR₇ R₁₁,NR₇ SO₂ R₁₁, CONR₇ SO₂ R₁₁, SO₃ R₇, SO₂ R₇, P(O)(OR₇)R₇, CN, -CO₂(CH₂)mC(O)N(R₆)₂, C(R₁₁)₂N(R₇)₂, C(O)N(R₆)₂, tetrazole or OR₆; R₉ isa bond, C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₁₋₁₀ alkylidene, C₂₋₁₀alkynylene, all of which may be linear or branched, or R₉ is phenylene,all of which may be unsubstituted or substituted by one or more OH,N(R₆)₂, COOH or halogen; R₁₀ is hydrogen; R₁₁ is hydrogen, Ar, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, all of which may be unsubstituted orsubstituted by one or more OH, CH₂ OH, N(R₆)₂ Br, Cl, I, or F; R₁₂ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₇ alkynyl; R₁₃ is divalent Ar,C₁₋₁₀ alkylene, C₁₋₁₀ alkylidene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene,all of which may be unsubstituted or substituted by one or two OH, CH₂OH, N(R₆)₂ Br, Cl, I, or F; X is (CH₂)_(n) or O; Y is CH₃ or X(CH₂)_(n)Ar; Ar is:

naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl,isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl,imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl,morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyol; all ofwhich may be unsubstituted or substituted by one or two OH, C₁₋₅ alkoxy,I, Br,F,Cl, —OC₁₋₄alkylphenyl, R₁₃CO₂R₇, C₁₋₄alkyl, —N(R₆)₂, —NH(CO)CH₃,—X(CH₂)_(n)R₈, —X —R₉—Y, pyridyl, phenyl or S(O)qC₁₋₅alkyl, providedthat when R₁₃, R₈ or Y are Ar, the Ar is not substituted by another Arwhich is further substituted by an yet another Ar; A is C═O, or(C(R₆)₂)_(m); B is —CH₂— or —O—; Z₁, Z₂ and Z₃ are indenpendentlyhydrogen,OH, C₁₋₈alkoxy, S(O)qC₁₋₈alkyl, N(R₆)₂, Br, F, I, Cl, NHCOR₆,—X —R₉—Y, —X(CH₂)_(n)R₈; or Z₁ and Z₂ together may be —O—A—O—oncontiguous carbons; q is zero, one or two; n is an integer from 0 tosix; m is 1, 2or 3; or a pharmaceutically acceptable salt thereof;provided that when Z₁, Z₂, or Z₃ is X(CH₂)_(n)R₈ and n is not 0, X isoxygen or when R₈ is OR₆ or CO₂H; provided P₁ is not CO₂H, C(R₆)₂COOH ortetrazole when P₂ is hydrogen and further provided R⁸ is not CN when Aris a moiety of formula (a) or (b) wherein A is CH₂ and B is O; and apharmaceutically acceptable carrier.
 2. A method of treatment ofdiseases caused by an excess of endothelin comprising administering to asubject in need thereof, an effective amount of an endothelin receptorantagonist of Formula I of claim
 1. 3. A method of treatinghypertension, renal failure or cerebrovascular disease which comprisesadministering to a subject in need thereof, an effective amount of acompound of of Formula I of claim
 1. 4. A method for the prophylaxis andtreatment of radiocontrast induced renal failure which comprisesadministering to a subject in need thereof, an effective amount of acompound of Formula I of claim
 1. 5. A method of treatment of congestiveheart failure which comprises administering to a subject in needthereof, an effective amount of a compound of Formula I of claim
 1. 6. Amethod of treatment of migraine which comprises administering to asubject in need thereof, an effective amount of a compound of Formula Iof claim
 1. 7. A method of treating restenosis which comprisesadministering to a subject in need thereof, an effective amount of acompound of Formula I of claim 1.